WO2017171048A1 - 早期膵がん又は膵がん前駆病変の検出キット又はデバイス及び検出方法 - Google Patents
早期膵がん又は膵がん前駆病変の検出キット又はデバイス及び検出方法 Download PDFInfo
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/112—Disease subtyping, staging or classification
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/118—Prognosis of disease development
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
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- C12Q2600/00—Oligonucleotides characterized by their use
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Definitions
- the present invention relates to an early pancreatic cancer or pancreas comprising a nucleic acid that can specifically bind to a specific miRNA, which is used for examining whether or not an early pancreatic cancer or pancreatic cancer precursor lesion is affected in a subject.
- the present invention relates to a kit or device for detecting cancer precursor lesions, and a method for detecting early pancreatic cancer or pancreatic cancer precursor lesions, comprising measuring the expression level of the miRNA using the nucleic acid.
- the pancreas is an exocrine gland that secretes pancreatic juice that is a digestive fluid and sends it through the pancreatic duct to the digestive tract, and also functions as an endocrine gland that secretes hormones such as insulin and glucagon into the blood.
- pancreas is surrounded by many organs such as the stomach, duodenum, small intestine, liver, gallbladder, so it is not only difficult to detect cancer early, but also has no subjective symptoms, progresses very quickly, and spreads to other organs It has the characteristics of causing cancer and has a very poor prognosis compared to other cancers.
- the cancer mortality statistics by region in Japan disclosed in 2011 by the National Cancer Center Information Center for Cancer Control (Tokyo, Japan), the number of deaths from pancreatic cancer is 28, With 829 people, the 5-year relative survival rate by region from 2003 to 2005 is lowest for pancreatic cancer, 7.1% for men and 6.9% for women.
- Non-Patent Document 1 the basics of pancreatic cancer treatment are performed by surgery, systemic chemotherapy, radiotherapy or a combination thereof depending on the degree of progression. Although surgery has been done because 15-20% of pancreatic cancer patients can be cured, most patients who have not undergone surgery are considered to have progressed locally or have metastasized.
- stage 1 The progression of pancreatic cancer by UICC (Unio Internationalis Contra Cancrum) is classified into stage 0, IA, IB, IIA, IIB, III, IVa, and IVb.
- Stage I-III accounts for more than half of 5-year survivors, and Stage IVa and Stage IVb account for over 70% of the progress at the time of diagnosis.
- the 5-year survival rate of pancreatic cancer is 45.8% for stage IA, 36.3% for stage IB, 29.4% for stage IIA, and 10.2 for stage IIB.
- stage III is 5.9%
- stage IV is 4.0%
- the prognosis of stage III and stage IV is extremely poor, so it is necessary to detect and treat pancreatic cancer at an early stage .
- abdominal ultrasonography is very useful as a simple and minimally invasive test for diagnosis of pancreatic cancer in outpatient care and screening.
- pancreatic cancer and pancreatic caudal lesions with small tumor diameters.
- the prevalence of pancreatic images found by abdominal ultrasonography in a normal health examination is about 1%, and the detection rate of pancreatic cancer is low, about 0.06% or less.
- tumor markers for detecting pancreatic cancer include antigens other than sugar chains such as CA19-9, Span-1, CA50, CA242, Kun-2, TAG-72, and urinary fucose as sugar chain antigens.
- CEA, POA, TPS and the like are known.
- cancer is suspected when the blood concentration is higher or lower than a predetermined reference value.
- a predetermined reference value is set to 5 ng / mL
- the CA19-9 reference value is set to 37 U / mL.
- Cancer including cancer is suspected.
- most tumor marker evaluations are for advanced pancreatic cancer, and early pancreatic cancer often does not show abnormal values.
- pancreatic cancer detection rate is low even when tumor markers and abdominal ultrasonography are performed at screening, and the implementation of these screenings for pancreatic cancer detection is problematic in terms of cost effectiveness.
- cystic diseases that occur in the pancreas are known to become malignant and progress to invasive cancer, and can be regarded as pancreatic cancer precursor lesions.
- the grade of malignancy of cystic disease is evaluated by cyst diameter, wall thickening, main pancreatic duct diameter, mural nodule, main pancreatic duct stenosis, lymphadenopathy, cystic lesion, etc.
- intraductal papillary mucinous tumor which is a type of cystic disease
- the prognosis is poor with 40.4% malignancy and 30.8% invasive cancer, so even if the malignancy at the time of detection is low, follow-up Or excision is recommended.
- Patent Documents 1 to 5 and Non-Patent Document 4 the expression level of microRNA (miRNA) in biological samples including blood, or the expression level of miRNA and other protein markers There is a report that pancreatic cancer is discriminated by combining with the expression level of.
- miRNA microRNA
- Patent Document 1 discloses a method for detecting pancreatic cancer by combining hsa-miR-125a-3p, hsa-miR-204-3p, and hsa-miR-3648 in blood with several other miRNAs. ing.
- Patent Document 2 discloses a method for detecting pancreatic cancer by combining miRNAs such as hsa-miR-1908-5p, hsa-miR-6729-5p, and hsa-miR-5195-3p in blood. .
- Patent Document 3 discloses a method for detecting pancreatic cancer by combining miR-23a-3p in blood with several tens of other miRNAs.
- Patent Document 4 includes hsa-miR-1268a, hsa-miR-939-5p, and hsa-miR-642b-3p as miRNAs whose expression levels are increased in the blood of pancreatic cancer patients compared to healthy subjects. A method for detecting pancreatic cancer in combination with several tens of other miRNAs and a method for evaluating the risk of developing pancreatic cancer are shown.
- Patent Document 5 discloses a method for detecting pancreatic cancer and pancreatic cancer precursor lesions by combining hsa-miR-296-5p in blood with several tens of other miRNAs, and the risk of developing pancreatic cancer. The method of evaluation is shown.
- Non-Patent Document 5 includes hsa-miR-638, hsa-miR-3196, hsa-miR-1225-3p, and the like as miRNAs whose expression level is increased in the blood of pancreatic cancer patients from healthy subjects. A method for detecting pancreatic cancer by combining several of these miRNAs has been shown.
- An object of the present invention is to find a novel early pancreatic cancer or pancreatic cancer precursor lesion tumor marker, and to effectively prevent early pancreatic cancer or pancreatic cancer precursor lesion using a nucleic acid capable of specifically binding to the marker. It is to provide a method that can be detected.
- tumor markers for detecting pancreatic cancer include, for example, CA19-9, Span-1, CA50, CA242, Cincinnatin-2, TAG-72, urine as sugar chain antigens.
- CEA, POA, TPS and the like are known as medium fucose and the like or antigens other than sugar chains.
- Pancreatic cancer detection sensitivity of these tumor markers is CA19-9 70-80%, Span-1 70-80%, Kun-2 50-60%, CEA 30-60%, CA50 60%
- specificity is not so high and false positives are also high at 20-30%, it is possible to erroneously detect other cancers and / or benign tumors and / or benign diseases of the pancreas and / or surrounding organs of the pancreas Sex is also conceivable.
- early pancreatic cancer detection sensitivity is generally low, and pancreatic cancer of 2 cm or less is not useful for detection of early pancreatic cancer because the CA19-9 positive rate is only 52%. .
- tumor markers based on sugar chain antigens are not suitable for some subjects because antigens are not produced in Lewis blood group negative cases and are false negative.
- detection rates by MRI and CT for intraductal papillary mucinous tumors, which are pancreatic cancer precursor lesions are not sufficient, 19.9% and 1.2-2.6%, respectively. The use of tumor markers is not recommended.
- pancreatic cancer is discriminated using the expression level of microRNA (miRNA) in the biological sample including blood as described below. It has not been put into practical use as a method for detecting cancer precursor lesions.
- miRNA microRNA
- Patent Document 1 discloses a method for detecting pancreatic cancer by combining miR-125a-3p, miR-204-3p, and miR-3648 in blood with several other miRNAs.
- a negative control group only healthy subjects are used, there is no description of cancers or benign diseases of organs other than the pancreas, and no specific method for detecting pancreatic cancer precursor lesions using blood is described. .
- Patent Document 2 discloses a method for detecting pancreatic cancer by combining miRNAs such as hsa-miR-1908-5p, hsa-miR-6729-5p and hsa-miR-5195-3p in blood.
- miRNAs such as hsa-miR-1908-5p, hsa-miR-6729-5p and hsa-miR-5195-3p in blood.
- Patent Document 3 discloses a method for detecting pancreatic cancer by combining hsa-miR-23a-3p in blood with other dozens of miRNAs. There is no description about detection performance such as sensitivity and specificity, there is no description about cancer other than the upper gastrointestinal tract around the pancreas as a negative control group for pancreatic cancer, and a method for detecting pancreatic cancer precursor lesions is also described Absent.
- Patent Document 4 detects pancreatic cancer and pancreatic cancer precursor lesions by combining hsa-miR-1268a, hsa-miR-939-5p, and hsa-miR-642b-3p with other dozens of miRNAs.
- detection performance such as specific accuracy, sensitivity, and specificity for pancreatic cancer, and description of cancer of organs other than pancreas as a negative control group for pancreatic cancer Nor.
- Patent Document 5 discloses a method for detecting pancreatic cancer and pancreatic cancer precursor lesions by combining hsa-miR-296-5p in blood with other dozens of miRNAs. There is no description of detection performance such as accuracy, sensitivity, specificity, etc., and we have not measured cancers or benign diseases of organs other than pancreas as a negative control group for pancreatic cancer precursor lesions. There is no mention of specificity.
- Non-Patent Document 5 includes hsa-miR-638, hsa-miR-3196, hsa-miR-1225-3p, and the like as miRNAs whose expression levels are increased in the blood of pancreatic cancer patients from healthy subjects, Although a method for detecting pancreatic cancer by combining several of these miRNAs has been shown, there is no description of cancer of organs other than the pancreas as a negative control group for pancreatic cancer.
- pancreatic cancer or pancreatic cancer precursor lesions the performance of existing tumor markers is low, or the performance and detection methods are not specifically shown for markers in the research stage When these are used, it is necessary to perform a wasteful additional test by misdetecting a healthy body as an early pancreatic cancer or pancreatic cancer precursor lesion patient, or overlook an early pancreatic cancer or pancreatic cancer precursor lesion patient. Loss of treatment opportunities can occur.
- measuring tens to hundreds of miRNAs increases the cost of testing, and is therefore difficult to use for large-scale screening such as medical examinations.
- collecting pancreatic tissue to measure tumor markers is not preferable because it is highly invasive to patients, and can be detected from blood that can be collected in a minimally invasive manner.
- pancreatic cancer or pancreatic cancer precursor lesion marker that can correctly distinguish patients from patients with early pancreatic cancer or pancreatic cancer precursor lesions and healthy subjects as healthy subjects.
- excision by early detection is the only curative treatment for pancreatic cancer, a highly sensitive early pancreatic cancer or pancreatic cancer precursor lesion marker is eagerly desired.
- the present inventors have found several genes that can be used as detection markers for early pancreatic cancer or pancreatic cancer precursor lesions from blood that can be collected in a minimally invasive manner. It has been found that early pancreatic cancer or pancreatic cancer precursor lesions can be detected significantly by using a nucleic acid that can be bound to the target, and the present invention has been completed.
- the present invention has the following features.
- miR-6784-5p is hsa-miR-6784-5p
- miR-1181 is hsa-miR-1181
- miR-671-5p is hsa-miR-671-5p
- miR-6857 -5p is hsa-miR-6857-5p
- miR-4276 is hsa-miR-4276
- miR-1914-3p is hsa-miR-1914-3p
- miR-149-3p is hsa-miR -149-3p
- miR-937-5p is hsa-miR-937-5p
- miR-4675 is hsa-miR-4675
- miR-6695-5p is hsa-miR-6695-5p
- MiR-4731-5p is hsa-miR-4731-5p
- miR-5090 is hsa- iR-5090
- miR-3620-5p
- polynucleotide according to any one of the following (a) to (e): (A) a polynucleotide comprising the base sequence represented by any one of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, or a base sequence in which u is t in the base sequence, variants thereof, A derivative, or a fragment thereof comprising 15 or more consecutive bases, (B) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, (C) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248 and 250 or a base sequence complementary to the base sequence in which u is t in the base sequence A variant thereof, a derivative thereof, or a fragment thereof comprising 15 or more consecutive bases, (D) a polynucleotide comprising the base sequence
- the above kit is another early pancreatic cancer or pancreatic cancer precursor lesion marker, miR-1908-5p, miR-6729-5p, miR-5195-3p, miR-638, miR-6125, miR -3178, miR-3196, miR-8069, miR-4723-5p, miR-4746-3p, miR-4689, miR-6816-5p, miR-6757-5p, miR-7109-5p, miR-6724-5p , MiR-1225-3p, miR-6875-5p, miR-7108-5p, miR-4508, miR-6085, miR-6679-5p, miR-642a-3p, miR-4695-5p, miR-7847-3p MiR-3197, miR-6769b-5p, miR-7641, miR-1 7-5p, miR-3185, miR-2861, miR-3940-5p, miR-1203, miR-615-5p, miR-4787-5p, miR-1343
- miR-1908-5p is hsa-miR-1908-5p
- miR-6729-5p is hsa-miR-6729-5p
- miR-5195-3p is hsa-miR-5195-3p
- MiR-638 is hsa-miR-638
- miR-6125 is hsa-miR-6125
- miR-3178 is hsa-miR-3178
- miR-3196 is hsa-miR-3196
- miR -8069 is hsa-miR-8069
- miR-4723-5p is hsa-miR-4723-5p
- miR-4746-3p is hsa-miR-4746-3p
- miR-4789 is hsa-miR -4689
- miR-6816-5p is hsa-miR-6816-5p
- MiR-6757-5p is hsa-miR
- miR-6784-5p miR-1181, miR-671-5p, miR-6857-5p, miR-4276, miR-1914-3p, miR, which are early pancreatic cancer or pancreatic cancer precursor lesion markers -149-3p, miR-937-5p, miR-4675, miR-6695-5p, miR-4731-5p, miR-5090, miR-3620-5p, miR-1343-5p, miR-6717-5p, miR -6825-5p, miR-6638-5p, miR-6769a-5p, miR-4728-5p, miR-652-5p, miR-4257, miR-6785-5p, miR-7110-5p, miR-6687-5p MiR-887-3p, miR-1228-5p, miR-5572, miR-67 2-5p, miR-4298, miR-6786-5p, miR-5010-5p, miR-6087, miR-6765-5p, miR,
- miR-6784-5p is hsa-miR-6784-5p
- miR-1181 is hsa-miR-1181
- miR-671-5p is hsa-miR-671-5p
- miR-6857 -5p is hsa-miR-6857-5p
- miR-4276 is hsa-miR-4276
- miR-1914-3p is hsa-miR-1914-3p
- miR-149-3p is hsa-miR -149-3p
- miR-937-5p is hsa-miR-937-5p
- miR-4675 is hsa-miR-4675
- miR-6695-5p is hsa-miR-6695-5p
- MiR-4731-5p is hsa-miR-4731-5p
- miR-5090 is hsa- iR-5090
- miR-3620-5p
- polynucleotide according to any one of the following (a) to (e): (A) a polynucleotide comprising the base sequence represented by any one of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, or a base sequence in which u is t in the base sequence, variants thereof, A derivative, or a fragment thereof comprising 15 or more consecutive bases, (B) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, (C) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248 and 250 or a base sequence complementary to the base sequence in which u is t in the base sequence A variant thereof, a derivative thereof, or a fragment thereof comprising 15 or more consecutive bases, (D) a polynucleotide comprising the
- the above device is another early pancreatic cancer or pancreatic cancer precursor lesion marker, miR-1908-5p, miR-6729-5p, miR-5195-3p, miR-638, miR-6125, miR -3178, miR-3196, miR-8069, miR-4723-5p, miR-4746-3p, miR-4689, miR-6816-5p, miR-6757-5p, miR-7109-5p, miR-6724-5p , MiR-1225-3p, miR-6875-5p, miR-7108-5p, miR-4508, miR-6085, miR-6679-5p, miR-642a-3p, miR-4695-5p, miR-7847-3p , MiR-3197, miR-6769b-5p, miR-7641, miR 187-5p, miR-3185, miR-2861, miR-3940-5p, miR-1203, miR-615-5p, miR-4787-5p, miR
- miR-1908-5p is hsa-miR-1908-5p
- miR-6729-5p is hsa-miR-6729-5p
- miR-5195-3p is hsa-miR-5195-3p
- MiR-638 is hsa-miR-638
- miR-6125 is hsa-miR-6125
- miR-3178 is hsa-miR-3178
- miR-3196 is hsa-miR-3196
- miR -8069 is hsa-miR-8069
- miR-4723-5p is hsa-miR-4723-5p
- miR-4746-3p is hsa-miR-4746-3p
- miR-4789 is hsa-miR -4689
- miR-6816-5p is hsa-miR-6816-5
- MiR-6757-5p is hsa-miR-
- MiR-6780b-5p is hsa-miR-6780b-5p
- MiR-6090 is hsa-miR-6090
- miR-6845-5p is hsa-miR-6845-5p
- miR-4741 is hsa-miR-4741
- miR-4467 is hsa-miR-4467.
- MiR-4707-5p is hsa-miR-4707-5p
- miR-4271 is hsa-miR-4271
- miR-4673 is hsa-miR-4673
- miR-3184-5p is hsa MiR-3184-5p
- miR-1469 is hsa-miR-1469
- miR-4640-5p is hsa-miR-4640-5p
- miR-663a is hsa-miR-663a
- miR -6791-5p is hsa-miR-6791-5p
- m R-6826-5p is hsa-miR-6826-5p
- miR-4433b-3p is hsa-miR-4433b-3p
- miR-1915-3p is hsa-miR-1915-3p
- miR- 4417 is hsa-miR-4417
- the subject is suffering from early pancreatic cancer or pancreatic cancer precursor lesion, or early pancreatic cancer or pancreatic cancer
- Early pancreas in a subject is assessed in vitro to be free of pre-cancerous lesions, thereby detecting the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions in the subject. For detecting cancer or pancreatic cancer precursor lesions.
- pancreatic cancer refers to invasive pancreatic ductal carcinoma. Specifically, papillary adenocarcinoma, tubular adenocarcinoma, poorly differentiated adenocarcinoma, adenocarcinoma of the pancreas, adenocarcinoma of the adenocarcinoma (adenocarcinoma) ), Anaplastic carcinoma, etc.
- Pancreatic Cancer Handling Rules 6th edition, revised edition, 2013, Japanese Pancreas Society, Kanehara Publishing (Tokyo, Japan), p27-28).
- pancreatic cancer precursor lesion refers to an exocrine neoplasm that is formed in the pancreas.
- serous cystic tumors SCNs
- serous cystadenomas SCA
- serous cystadenocarcinoma SCC
- mucinous cystic tumors Mucinocystic mucinous tumors
- MCA Mucinous Cystadenocarcinoma
- IPMNs Intraductal papillary mucinous tumor
- IPMC Intraductal papillary-mucinous carcinoma
- the “degree of progression of pancreatic cancer” is classified into stage 0, IA, IB, IIA, IIB, III, IVa, and IVb according to the main tumor local progression degree, lymph node metastasis, distant metastasis, and the like ( Pancreatic Cancer Handling Regulations, 6th edition, revised edition, 2013, Japan Pancreas Society, Kanehara Publishing (Tokyo, Japan), p55-57).
- pancreatic cancer refers to pancreatic cancer of stage 0, IA, IB, IIA, IIB.
- advanced pancreatic cancer refers to stage III, IVa, or IVb pancreatic cancer.
- cancer disease refers to a disease of a non-malignant tumor related to an organ.
- nucleotide As used herein, “nucleotide”, “polynucleotide”, “DNA”, “RNA” and the like are indicated by abbreviations such as “Guidelines for creating specifications including base sequences or amino acid sequences”. (Edited by the Japan Patent Office) and customary in this technical field.
- polynucleotide is used for nucleic acids including RNA, DNA, and RNA / DNA (chimera).
- the DNA includes any of cDNA, genomic DNA, and synthetic DNA.
- the RNA includes total RNA, mRNA, rRNA, miRNA, siRNA, snoRNA, snRNA, non-coding RNA, and synthetic RNA.
- synthetic DNA and “synthetic RNA” are artificially generated using, for example, an automatic nucleic acid synthesizer based on a predetermined base sequence (which may be either a natural sequence or a non-natural sequence). It refers to the prepared DNA and RNA.
- non-natural sequence is intended to be used in a broad sense, and is a sequence (for example, including one or more nucleotide substitutions, deletions, insertions and / or additions) that differs from the natural sequence. That is, it includes a mutant sequence), a sequence containing one or more modified nucleotides (ie, a modified sequence), and the like.
- the polynucleotide is used interchangeably with the nucleic acid.
- a “fragment” is a polynucleotide having a base sequence of a continuous part of a polynucleotide, and desirably has a length of 15 bases or more, preferably 17 bases or more, more preferably 19 bases or more. .
- RNA and double-stranded DNA include not only RNA and double-stranded DNA, but also each single-stranded DNA such as positive strand (or sense strand) or complementary strand (or antisense strand) constituting the same. It is intended to be used.
- the length is not particularly limited.
- “gene” refers to double-stranded DNA including human genomic DNA, single-stranded DNA (positive strand), and single-stranded DNA having a sequence complementary to the positive strand (complementary). Strand) (eg, cDNA), microRNA (miRNA), and fragments thereof, and any of their transcripts.
- Strand eg, cDNA
- miRNA microRNA
- the “gene” is not limited to a “gene” represented by a specific nucleotide sequence (or sequence number), but also RNAs having biological functions equivalent to RNA encoded by these, for example, homologs (ie, homologs). Or an ortholog), variants such as genetic polymorphisms, and “nucleic acids” encoding derivatives.
- nucleic acid encoding such homologue, variant or derivative is, for example, the base sequence represented by any of SEQ ID NOs: 1 to 812 under the stringent conditions described later, or the base A “nucleic acid” having a base sequence that hybridizes with a complementary sequence of the base sequence in which u is t in the sequence can be mentioned.
- the “gene” does not ask whether the functional region is different, and may include, for example, an expression control region, a coding region, an exon, or an intron. Further, the “gene” may be contained in the cell, may be released outside the cell and may be present alone, or may be encapsulated in a vesicle called an exosome.
- exosome is a vesicle encased in a lipid bilayer secreted from a cell. Exosomes are derived from multivesicular endosomes, and when released to the extracellular environment, they may contain biological substances such as “genes” such as RNA and DNA and proteins. It is known that exosomes are contained in body fluids such as blood, serum, plasma and lymph.
- RNA refers to RNA synthesized using a DNA sequence of a gene as a template.
- RNA is synthesized in such a manner that RNA polymerase binds to a site called a promoter located upstream of the gene and ribonucleotides are bound to the 3 'end so as to be complementary to the DNA base sequence.
- This RNA includes not only the gene itself but also the entire sequence from the transcription start point to the end of the poly A sequence, including the expression control region, coding region, exon or intron.
- microRNA is a protein complex that is transcribed as a hairpin-like RNA precursor, cleaved by a dsRNA cleaving enzyme having RNase III cleaving activity, and called RISC. 15-25 base non-coding RNA that is incorporated into and is involved in the translational repression of mRNA.
- miRNA is not limited to “miRNA” represented by a specific nucleotide sequence (or sequence number), but also a precursor of the “miRNA” (pre-miRNA, pri-miRNA), and Also included are miRNAs that have equivalent biological functions, such as homologs (ie, homologs or orthologs), variants such as genetic polymorphisms, and derivatives. Such precursors, homologues, mutants or derivatives can be specifically identified by miRBase release 20 (http://www.mirbase.org/) under stringent conditions described later. And “miRNA” having a base sequence that hybridizes with a complementary sequence of any one of the specific base sequences represented by any of SEQ ID NOs: 1 to 812.
- miRNA used herein may be a gene product of a miR gene, and such a gene product is a mature miRNA (for example, 15 to 15 involved in the suppression of translation of mRNA as described above). 25-base, or 19-25 base non-coding RNA) or miRNA precursors (eg, pre-miRNA or pri-miRNA as described above).
- the “probe” includes a polynucleotide used for specifically detecting RNA produced by gene expression or a polynucleotide derived therefrom and / or a polynucleotide complementary thereto.
- the “primer” includes a polynucleotide that specifically recognizes and amplifies RNA generated by gene expression or a polynucleotide derived therefrom and / or a polynucleotide complementary thereto.
- a complementary polynucleotide is a polynucleotide comprising a base sequence defined by any of SEQ ID NOs: 1 to 812 or a base sequence in which u is t in the base sequence.
- the base sequence is complementary to the full-length sequence or a partial sequence thereof (for convenience, this is referred to as the positive strand) based on the base pair relationship such as A: T (U), G: C. Means polynucleotide.
- a polynucleotide comprising a complementary base sequence to the base sequence represented by any of SEQ ID NOs: 1 to 812 or a base sequence in which u is t in the base sequence is basically understood in the same manner.
- stringent conditions means a nucleic acid probe that is detectable to a greater extent than other sequences (eg, average of background measurements + standard error of background measurements ⁇ measured value of 2 or more). ) And the conditions for hybridizing to the target sequence. Stringent conditions are sequence-dependent and depend on the environment in which hybridization is performed. By controlling the stringency of the hybridization and / or wash conditions, target sequences that are 100% complementary to the nucleic acid probe can be identified. Specific examples of “stringent conditions” will be described later.
- the “Tm value” means a temperature at which a double-stranded portion of a polynucleotide is denatured into a single strand and the double strand and the single strand are present at a ratio of 1: 1.
- variant refers to a natural variant caused by polymorphism, mutation, etc., or any nucleotide sequence of SEQ ID NOs: 1 to 812, or u in the nucleotide sequence in the case of nucleic acid.
- a variant comprising a deletion, substitution, addition or insertion of one or more (eg, 1 to several) bases in the base sequence of t, or a partial sequence thereof, or each of the base sequences or a partial sequence thereof 90% or more, about 95% or more, about 97% or more, about 98% or more, about 99% or more, a variant exhibiting% identity, or a polynucleotide or oligonucleotide containing the nucleotide sequence or a partial sequence thereof as defined above It means a nucleic acid that hybridizes under stringent conditions.
- “several” means an integer of about 10, 9, 8, 7, 6, 5, 4, 3 or 2.
- a mutant can be prepared by using a well-known technique such as a site-directed mutagenesis method or a mutagenesis method using a PCR method.
- % identity can be determined using the above-described BLAST or FASTA protein or gene search system with or without introducing a gap (Zheng Zhang et al., 2000, J. Comput. Biol., 7, p203-214; Altschul, SF et al., 1990, Journal of Molecular Biology, 215, p403-410; Pearson, WR, et al., 1988, Proc. Natl. Acad. Sci. U. S. A., vol.
- the term “derivative” refers to a modified nucleic acid, a non-limiting group such as a labeled derivative such as a fluorophore, a modified nucleotide (for example, a halogen, an alkyl such as methyl, an alkoxy such as methoxy, a group such as thio, carboxymethyl, etc.
- a derivative containing PNA peptide nucleic acid; Nielsen, PE, etc.). 1991, Science, 254, p1497-500
- LNA locked nucleic acid; Obika, S. et al., 1998, Tetrahedron Lett., 39, p5401-5404), etc. .
- a “nucleic acid” that can specifically bind to a polynucleotide selected from miRNA that is the aforementioned early pancreatic cancer or pancreatic cancer precursor lesion marker is a synthesized or prepared nucleic acid, specifically Includes a “nucleic acid probe” or “primer” to detect the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions in a subject, or to suffer from early pancreatic cancer or pancreatic cancer precursor lesions
- a “nucleic acid probe” or “primer” to detect the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions in a subject, or to suffer from early pancreatic cancer or pancreatic cancer precursor lesions
- To diagnose the presence or absence of disease, the extent of disease, the presence or absence of improvement in early pancreatic cancer or pancreatic cancer precursor lesions, the sensitivity to treatment of early pancreatic cancer or pancreatic cancer precursor lesions, or early pancreatic cancer It is used directly or indirectly to screen candidate substances useful for
- the term “detection” can be replaced by the term inspection, measurement, determination, or determination support. Further, in this specification, the term “evaluation” is used in a meaning including supporting diagnosis or evaluation based on a test result or a measurement result.
- subject includes humans, primates including chimpanzees, pet animals such as dogs and cats, livestock animals such as cows, horses, sheep and goats, rodents such as mice and rats, Mammals such as animals raised in zoos.
- a preferred subject is a human.
- “Healthy body” also means an animal that is such a mammal and does not suffer from the cancer to be detected.
- a preferred healthy body is a human.
- P or “P value” refers to the probability that, in a statistical test, a statistic more extreme than the statistic actually calculated from the data under the null hypothesis is observed. Indicates. Therefore, it can be considered that the smaller the “P” or “P value”, the more significant the difference between the comparison objects.
- sensitivity means a value of (number of true positives) / (number of true positives + number of false negatives). High sensitivity makes it possible to detect early pancreatic cancer or pancreatic cancer precursor lesions early, leading to complete removal of the cancerous part and a reduction in the recurrence rate.
- specificity means (number of true negatives) / (number of true negatives + number of false positives). If the specificity is high, it is possible to prevent a normal body from being misidentified as an early pancreatic cancer or pancreatic cancer precursor lesion patient, and to reduce unnecessary burden on the patient and medical costs.
- accuracy means a value of (number of true positives + number of true negatives) / (number of all cases). The accuracy indicates the rate at which the discrimination results for all the samples are correct, and is a first index for evaluating the detection performance.
- the “specimen” to be determined, detected or diagnosed in this specification refers to the occurrence of early pancreatic cancer or pancreatic cancer precursor lesions, early pancreatic cancer or pancreatic cancer precursor lesions, or early pancreatic cancer.
- it refers to a tissue or biomaterial in which the gene of the present invention changes in expression as a result of the therapeutic effect on pancreatic cancer precursor lesions.
- pancreatic tissues and their surrounding vessels, lymph nodes and organs, organs suspected of metastasis, skin, and body fluids such as blood, urine, saliva, sweat, and tissue exudates, and serum and plasma prepared from blood Others include stool and hair.
- RNA and miRNA include a biological sample extracted from these, specifically genes such as RNA and miRNA.
- hsa-miR-6784-5p gene or “hsa-miR-6784-5p” refers to the hsa-miR-6784-5p gene described in SEQ ID NO: 1 (miRBase Accession No. 1). MIMAT0027468) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6784-5p” is known as “hsa-mir-6784” (miRBase Accession No. MI0022629, SEQ ID NO: 251) having a hairpin-like structure as a precursor.
- hsa-miR-1181 gene or “hsa-miR-1181” refers to the hsa-miR-1181 gene (miRBase Accession No. MIMAT0005826) described in SEQ ID NO: 2 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Subramanian S et al., 2008, Oncogene, 27, p2015-2026. As for “hsa-miR-1181”, “hsa-mir-1181” (miRBase Accession No. MI0006274, SEQ ID NO: 252) having a hairpin-like structure as a precursor is known.
- hsa-miR-671-5p gene or “hsa-miR-671-5p” refers to the hsa-miR-671-5p gene (miRBase Accession No. 3) described in SEQ ID NO: 3. MIMAT0003880) and other species homologs or orthologs.
- the gene can be obtained by the method described in Berezikov E et al., 2006, Genome Res, 16, p1289-1298.
- “hsa-miR-671-5p” is known as “hsa-mir-671” (miRBase Accession No. MI0003760, SEQ ID NO: 253) having a hairpin-like structure as a precursor.
- hsa-miR-6857-5p gene or “hsa-miR-6857-5p” refers to the hsa-miR-6857-5p gene described in SEQ ID NO: 4 (miRBase Accession No. MIMAT0027614) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6857-5p” is known as “hsa-mir-6857” (miRBase Accession No. MI0022703, SEQ ID NO: 254) having a hairpin-like structure as a precursor.
- hsa-miR-4276 gene or “hsa-miR-4276” refers to the hsa-miR-4276 gene (miRBase Accession No. MIMAT0016904) described in SEQ ID NO: 5 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. As for “hsa-miR-4276”, “hsa-mir-4276” (miRBase Accession No. MI0015882, SEQ ID NO: 255) having a hairpin-like structure as a precursor is known.
- hsa-miR-1914-3p gene or “hsa-miR-1914-3p” refers to the hsa-miR-1914-3p gene (miRBase Accession No. 6) described in SEQ ID NO: 6. MIMAT0007890) and other species homologs or orthologs.
- the gene can be obtained by the method described in Bar M et al., 2008, Stem Cells, 26, p2496-2505.
- “hsa-miR-1914-3p” is known as “hsa-mir-1914” (miRBase Accession No. MI0008335, SEQ ID NO: 256) having a hairpin-like structure as a precursor.
- hsa-miR-149-3p gene or “hsa-miR-149-3p” refers to the hsa-miR-149-3p gene described in SEQ ID NO: 7 (miRBase Accession No. MIMAT0004609) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Lagos-Quintana M et al., 2002, Curr Biol, 12, p735-739.
- “hsa-miR-149-3p” is known as “hsa-mir-149” (miRBase Accession No. MI0000478, SEQ ID NO: 257) having a hairpin-like structure as a precursor.
- hsa-miR-937-5p gene or “hsa-miR-937-5p” refers to the hsa-miR-937-5p gene described in SEQ ID NO: 8 (miRBase Accession No. MIMAT0022938) and other species homologs or orthologs.
- the gene can be obtained by the method described in Lui WO et al., 2007, Cancer Res, Vol. 67, p6031-6043.
- “hsa-miR-937-5p” is known as “hsa-mir-937” (miRBase Accession No. MI0005759, SEQ ID NO: 258) having a hairpin-like structure as a precursor.
- hsa-miR-4675 gene or “hsa-miR-4675” refers to the hsa-miR-4675 gene (miRBase Accession No. MIMAT0019757) described in SEQ ID NO: 9 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4675”, “hsa-mir-4675” (miRBase Accession No. MI0017306, SEQ ID NO: 259) having a hairpin-like structure as a precursor is known.
- hsa-miR-6695-5p gene or “hsa-miR-6695-5p” refers to the hsa-miR-6695-5p gene described in SEQ ID NO: 10 (miRBase Accession No. MIMAT0027490) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6695-5p “hsa-mir-6695” (miRBase Accession No. MI0022640, SEQ ID NO: 260) having a hairpin-like structure as a precursor is known.
- hsa-miR-4731-5p gene or “hsa-miR-4731-5p” refers to the hsa-miR-4731-5p gene described in SEQ ID NO: 11 (miRBase Accession No. 1). MIMAT0019853) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4731-5p “hsa-mir-4731” (miRBase Accession No. MI0017368, SEQ ID NO: 261) having a hairpin-like structure as a precursor is known.
- hsa-miR-5090 gene or “hsa-miR-5090” refers to the hsa-miR-5090 gene (miRBase Accession No. MIMAT0021082) described in SEQ ID NO: 12 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Ding N et al., 2011, J Radiat Res, 52, p425-432. As for “hsa-miR-5090”, “hsa-mir-5090” (miRBase Accession No. MI0017979, SEQ ID NO: 262) having a hairpin-like structure as a precursor is known.
- hsa-miR-3620-5p gene or “hsa-miR-3620-5p” refers to the hsa-miR-3620-5p gene described in SEQ ID NO: 13 (miRBase Accession No. MIMAT0022967) and other species homologs or orthologs.
- the gene can be obtained by the method described in Witten D et al., 2010, BMC Biol, Vol. 8, p58.
- hsa-mir-3620 miRBase Accession No. MI0016011, SEQ ID NO: 263 having a hairpin-like structure as a precursor is known.
- hsa-miR-1343-5p gene or “hsa-miR-1343-5p” refers to the hsa-miR-1343-5p gene described in SEQ ID NO: 14 (miRBase Accession No. 1). MIMAT0027038) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- “Hsa-miR-1343-5p” is known as “hsa-mir-1343” (miRBase Accession No. MI0017320, SEQ ID NO: 264) having a hairpin-like structure as a precursor.
- hsa-miR-6717-5p gene or “hsa-miR-6717-5p” refers to the hsa-miR-6717-5p gene (miRBase Accession No. 5) described in SEQ ID NO: 15. MIMAT00258446) and other species homologs or orthologs.
- the gene can be obtained by the method described in Li Y et al., 2012, Gene, 497, p330-335.
- “Hsa-miR-6717-5p” is known as “hsa-mir-6717” (miRBase Accession No. MI0022551, SEQ ID NO: 265) having a hairpin-like structure as a precursor.
- hsa-miR-6825-5p gene or “hsa-miR-6825-5p” refers to the hsa-miR-6825-5p gene described in SEQ ID NO: 16 (miRBase Accession No. MIMAT0027550) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6825-5p “hsa-mir-6825” (miRBase Accession No. MI0022670, SEQ ID NO: 266) having a hairpin-like structure as a precursor is known.
- hsa-miR-6738-5p gene or “hsa-miR-6738-5p” refers to the hsa-miR-6738-5p gene described in SEQ ID NO: 17 (miRBase Accession No. MIMAT0027377) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6738-5p “hsa-mir-6738” (miRBase Accession No. MI0022583, SEQ ID NO: 267) having a hairpin-like structure as a precursor is known.
- hsa-miR-6769a-5p gene or “hsa-miR-6769a-5p” refers to the hsa-miR-6769a-5p gene described in SEQ ID NO: 18 (miRBase Accession No. MIMAT0027438) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6769a-5p “hsa-mir-6769a” (miRBase Accession No. MI0022614, SEQ ID NO: 268) having a hairpin-like structure as a precursor is known.
- hsa-miR-4728-5p gene or “hsa-miR-4728-5p” refers to the hsa-miR-4728-5p gene described in SEQ ID NO: 19 (miRBase Accession No. MIMAT0019849) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4728-5p “hsa-mir-4728” (miRBase Accession No. MI0017365, SEQ ID NO: 269) having a hairpin-like structure as a precursor is known.
- hsa-miR-652-5p gene or “hsa-miR-652-5p” refers to the hsa-miR-652-5p gene described in SEQ ID NO: 20 (miRBase Accession No. MIMAT0022709) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692.
- “hsa-miR-652-5p” is known as “hsa-mir-652” (miRBase Accession No. MI0003667, SEQ ID NO: 270) having a hairpin-like structure as a precursor.
- hsa-miR-4257 gene or “hsa-miR-4257” refers to the hsa-miR-4257 gene (miRBase Accession No. MIMAT0016878) described in SEQ ID NO: 21 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. Also, “hsa-miR-4257” is known as “hsa-mir-4257” (miRBase Accession No. MI0015856, SEQ ID NO: 271) having a hairpin-like structure as a precursor.
- hsa-miR-6785-5p gene or “hsa-miR-6785-5p” refers to the hsa-miR-6785-5p gene (miRBase Accession No. MIMAT0027470) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6785-5p is known as “hsa-mir-6785” (miRBase Accession No. MI0022630, SEQ ID NO: 272) having a hairpin-like structure as a precursor.
- hsa-miR-7110-5p gene or “hsa-miR-7110-5p” refers to the hsa-miR-7110-5p gene described in SEQ ID NO: 23 (miRBase Accession No. MIMAT0028117) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-7110-5p is known as “hsa-mir-7110” (miRBase Accession No. MI0022961, SEQ ID NO: 273) having a hairpin-like structure as a precursor.
- hsa-miR-687-5p gene or “hsa-miR-6887-5p” refers to the hsa-miR-6887-5p gene (miRBase Accession No. MIMAT0027674) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6877p is known as “hsa-mir-6687” (miRBase Accession No. MI0022734, SEQ ID NO: 274) having a hairpin-like structure as a precursor.
- hsa-miR-887-3p gene or “hsa-miR-887-3p” refers to the hsa-miR-887-3p gene described in SEQ ID NO: 25 (miRBase Accession No. MIMAT0004951) and other species homologs or orthologs.
- the gene can be obtained by the method described in Berezikov E et al., 2006, Genome Res, 16, p1289-1298.
- hsa-miR-887-3p “hsa-mir-887” (miRBase Accession No. MI0005562, SEQ ID NO: 275) having a hairpin-like structure as a precursor is known.
- hsa-miR-1228-5p gene or “hsa-miR-1228-5p” refers to the hsa-miR-1228-5p gene (miRBase Accession No. MIMAT0005582) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336.
- hsa-miR-1228-5p is known as “hsa-mir-1228” (miRBase Accession No. MI0006318, SEQ ID NO: 276) having a hairpin-like structure as a precursor.
- hsa-miR-5572 gene or “hsa-miR-5572” refers to the hsa-miR-5572 gene (miRBase Accession No. MIMAT0022260) described in SEQ ID NO: 27 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Tandon M et al., 2012, Oral Dis, Vol. 18, p127-131. As for “hsa-miR-5572”, “hsa-mir-5572” (miRBase Accession No. MI0019117, SEQ ID NO: 277) having a hairpin-like structure as a precursor is known.
- hsa-miR-6782-5p gene or “hsa-miR-6782-5p” refers to the hsa-miR-6782-5p gene described in SEQ ID NO: 28 (miRBase Accession No. MIMAT0027464) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6782-5p “hsa-mir-6682” (miRBase Accession No. MI0022627, SEQ ID NO: 278) having a hairpin-like structure as a precursor is known.
- hsa-miR-4298 gene or “hsa-miR-4298” refers to the hsa-miR-4298 gene (miRBase Accession No. MIMAT0016852) described in SEQ ID NO: 29 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. Also, “hsa-miR-4298” is known as “hsa-mir-4298” (miRBase Accession No. MI0015830, SEQ ID NO: 279) having a hairpin-like structure as a precursor.
- hsa-miR-6786-5p gene or “hsa-miR-6786-5p” refers to the hsa-miR-6786-5p gene described in SEQ ID NO: 30 (miRBase Accession No. MIMAT0027472) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6786-5p” is known as “hsa-mir-6786” (miRBase Accession No. MI0022631, SEQ ID NO: 280) having a hairpin-like structure as a precursor.
- hsa-miR-5010-5p gene or “hsa-miR-5010-5p” refers to the hsa-miR-5010-5p gene described in SEQ ID NO: 31 (miRBase Accession No. MIMAT0021043) and other species homologs or orthologs. The gene can be obtained by the method described in Hansen TB et al., 2011, RNA Biol, Vol. 8, p378-383.
- “hsa-miR-5010-5p” is known as “hsa-mir-5010” (miRBase Accession No. MI0017878, SEQ ID NO: 281) having a hairpin-like structure as a precursor.
- hsa-miR-6087 gene or “hsa-miR-6087” refers to the hsa-miR-6087 gene (miRBase Accession No. MIMAT0023712) described in SEQ ID NO: 32 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Yoo JK et al., 2012, Stem Cells Dev, 21, p2049-2057. As for “hsa-miR-6087”, “hsa-mir-6087” (miRBase Accession No. MI0020364, SEQ ID NO: 282) having a hairpin-like structure as a precursor is known.
- hsa-miR-6765-5p gene or “hsa-miR-6765-5p” refers to the hsa-miR-6765-5p gene described in SEQ ID NO: 33 (miRBase Accession No. MIMAT0027430) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6765-5p “hsa-mir-6765” (miRBase Accession No. MI0022610, SEQ ID NO: 283) having a hairpin-like structure as a precursor is known.
- hsa-miR-6732-5p gene or “hsa-miR-6732-5p” refers to the hsa-miR-6732-5p gene described in SEQ ID NO: 34 (miRBase Accession No. MIMAT0027365) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6732-5p “hsa-mir-6732” (miRBase Accession No. MI0022577, SEQ ID NO: 284) having a hairpin-like structure as a precursor is known.
- hsa-miR-6787-5p gene or “hsa-miR-6787-5p” refers to the hsa-miR-6787-5p gene (miRBase Accession No. 5) described in SEQ ID NO: 35. MIMAT0027474) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6787-5p “hsa-mir-6787” (miRBase Accession No. MI0022632, SEQ ID NO: 285) having a hairpin-like structure as a precursor is known.
- hsa-miR-6737-5p gene or “hsa-miR-6737-5p” refers to the hsa-miR-6737-5p gene described in SEQ ID NO: 36 (miRBase Accession No. MIMAT0027375) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6737-5p “hsa-mir-6737” (miRBase Accession No. MI0022582, SEQ ID NO: 286) having a hairpin-like structure as a precursor is known.
- hsa-miR-128-2-5p gene or “hsa-miR-128-2-5p” refers to the hsa-miR-128-2-5p described in SEQ ID NO: 37. Genes (miRBBase Accession No. MIMAT0031095) and other species homologues or orthologues are included. The gene can be obtained by the method described in Lagos-Quintana M et al., 2002, Curr Biol, 12, p735-739. Also, “hsa-miR-128-2-5p” is known as “hsa-mir-128-2” (miRBase Accession No. MI000027, SEQ ID NO: 287) having a hairpin-like structure as a precursor.
- hsa-miR-4270 gene or “hsa-miR-4270” refers to the hsa-miR-4270 gene (miRBase Accession No. MIMAT0016900) described in SEQ ID NO: 38 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. As for “hsa-miR-4270”, “hsa-mir-4270” (miRBase Accession No. MI0015878, SEQ ID NO: 288) having a hairpin-like structure as a precursor is known.
- hsa-miR-6861-5p gene or “hsa-miR-6861-5p” refers to the hsa-miR-6861-5p gene described in SEQ ID NO: 39 (miRBase Accession No. MIMAT0027623) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6861-5p “hsa-mir-6861” (miRBase Accession No. MI0022708, SEQ ID NO: 289) having a hairpin-like structure as a precursor is known.
- hsa-miR-6756-5p gene or “hsa-miR-6756-5p” refers to the hsa-miR-6756-5p gene described in SEQ ID NO: 40 (miRBase Accession No. MIMAT0027412) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6756-5p “hsa-mir-6756” (miRBase Accession No. MI0022601, SEQ ID NO: 290) having a hairpin-like structure as a precursor is known.
- hsa-miR-1229-5p gene or “hsa-miR-1229-5p” refers to the hsa-miR-1229-5p gene described in SEQ ID NO: 41 (miRBase Accession No. MIMAT0022942) and other species homologs or orthologs are included.
- the gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336.
- hsa-miR-1229-5p “hsa-mir-1229” (miRBase Accession No. MI0006319, SEQ ID NO: 291) having a hairpin-like structure as a precursor is known.
- hsa-miR-6891-5p gene or “hsa-miR-6891-5p” refers to the hsa-miR-6891-5p gene described in SEQ ID NO: 42 (miRBase Accession No. MIMAT0027682) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6891-5p “hsa-mir-6891” (miRBase Accession No. MI0022738, SEQ ID NO: 292) having a hairpin-like structure as a precursor is known.
- hsa-miR-6848-5p gene or “hsa-miR-6848-5p” refers to the hsa-miR-6848-5p gene described in SEQ ID NO: 43 (miRBase Accession No. MIMAT0027596) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6848-5p “hsa-mir-6848” (miRBase Accession No. MI0022694, SEQ ID NO: 293) having a hairpin-like structure as a precursor is known.
- hsa-miR-1237-5p gene or “hsa-miR-1237-5p” refers to the hsa-miR-1237-5p gene described in SEQ ID NO: 44 (miRBase Accession No. MIMAT0022946) and other species homologs or orthologs. The gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336.
- “hsa-miR-1237-5p” is known as “hsa-mir-1237” (miRBase Accession No. MI0006327, SEQ ID NO: 294) having a hairpin-like structure as a precursor.
- hsa-miR-30c-1-3p gene or “hsa-miR-30c-1-3p” refers to the hsa-miR-30c-1-3p described in SEQ ID NO: 45. Genes (miRBBase Accession No. MIMAT0004674) and other species homologues or orthologues are included. The gene can be obtained by the method described in Lagos-Quintana M et al., 2002, Curr Biol, 12, p735-739. Further, “hsa-miR-30c-1-3p” is known as “hsa-mir-30c-1” (miRBase Accession No. MI000036, SEQ ID NO: 295) having a hairpin-like structure as a precursor.
- hsa-miR-1233-5p gene or “hsa-miR-1233-5p” refers to the hsa-miR-1233-5p gene (miRBase Accession No. MIMAT0022943) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336.
- “Hsa-miR-1233-5p” has a hairpin-like structure as its precursor, “hsa-mir-1233-1, hsa-mir-12233-2” (miRBase Accession No. MI0006323, MI0015973, SEQ ID NO: 296,297) are known.
- hsa-miR-211-3p gene or “hsa-miR-211-3p” refers to the hsa-miR-211-3p gene described in SEQ ID NO: 47 (miRBase Accession No. MIMAT0022694) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Lim LP et al., 2003, Science, 299, p1540.
- “hsa-miR-211-3p” is known as “hsa-mir-211” (miRBase Accession No. MI000027, SEQ ID NO: 298) having a hairpin-like structure as a precursor.
- hsa-miR-4758-5p gene or “hsa-miR-4758-5p” refers to the hsa-miR-4758-5p gene described in SEQ ID NO: 48 (miRBase Accession No. MIMAT0019903) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4758-5p “hsa-mir-4758” (miRBase Accession No. MI0017399, SEQ ID NO: 299) having a hairpin-like structure as a precursor is known.
- hsa-miR-614 gene or “hsa-miR-614” refers to the hsa-miR-614 gene (miRBase Accession No. MIMAT0003282) described in SEQ ID NO: 49 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692. As for “hsa-miR-614”, “hsa-mir-614” (miRBase Accession No. MI0003627, SEQ ID NO: 300) having a hairpin-like structure as a precursor is known.
- hsa-miR-6746-5p gene or “hsa-miR-6746-5p” refers to the hsa-miR-6746-5p gene described in SEQ ID NO: 50 (miRBase Accession No. MIMAT0027392) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6746-5p” is known as “hsa-mir-6746” (miRBase Accession No. MI0022591, SEQ ID NO: 301) having a hairpin-like structure as a precursor.
- hsa-miR-1915-5p gene or “hsa-miR-1915-5p” refers to the hsa-miR-1915-5p gene (miRBase Accession No. 5) described in SEQ ID NO: 51. MIMAT0007891) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Bar M et al., 2008, Stem Cells, 26, p2496-2505.
- “Hsa-miR-1915-5p” is known as “hsa-mir-1915” (miRBase Accession No. MI0008336, SEQ ID NO: 302) having a hairpin-like structure as a precursor.
- hsa-miR-4688 gene or “hsa-miR-4688” refers to the hsa-miR-4688 gene (miRBase Accession No. MIMAT0019777) described in SEQ ID NO: 52 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4688”, “hsa-mir-4688” (miRBase Accession No. MI0017321, SEQ ID NO: 303) having a hairpin-like structure as a precursor is known.
- hsa-miR-3917 gene or “hsa-miR-3913” refers to the hsa-miR-3917 gene (miRBase Accession No. MIMAT0018191) described in SEQ ID NO: 53 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Creighton CJ et al., 2010, PLoS One, 5, e9637. Also, “hsa-miR-3917” is known as “hsa-mir-3917” (miRBase Accession No. MI0016423, SEQ ID NO: 304) having a hairpin-like structure as a precursor.
- hsa-miR-5787 gene or “hsa-miR-5787” refers to the hsa-miR-5787 gene (miRBase Accession No. MIMAT0023252) described in SEQ ID NO: 54 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Yoo H et al., 2011, Biochem Biophys Res Commun, 415, p567-572.
- hsa-miR-5787 is known as “hsa-mir-5787” (miRBase Accession No. MI0019797, SEQ ID NO: 305) having a hairpin-like structure as a precursor.
- hsa-miR-4632-5p gene or “hsa-miR-4632-5p” refers to the hsa-miR-4632-5p gene (miRBase Accession No. 5) described in SEQ ID NO: 55. MIMAT0022977) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- “hsa-miR-4632-5p” is known as “hsa-mir-4632” (miRBase Accession No. MI0017259, SEQ ID NO: 306) having a hairpin-like structure as a precursor.
- hsa-miR-6126 gene or “hsa-miR-6126” refers to the hsa-miR-6126 gene (miRBase Accession No. MIMAT0024599) described in SEQ ID NO: 56 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Smith JL et al., 2012, J Virol, 86, p5278-5287. Also, “hsa-miR-6126” is known as “hsa-mir-6126” (miRBase Accession No. MI0021260, SEQ ID NO: 307) having a hairpin-like structure as a precursor.
- hsa-miR-135a-3p gene or “hsa-miR-135a-3p” refers to the hsa-miR-135a-3p gene described in SEQ ID NO: 57 (miRBase Accession No. MIMAT0004595) and other species homologs or orthologs.
- the gene can be obtained by the method described in Lagos-Quintana M et al., 2002, Curr Biol, 12, p735-739.
- hsa-miR-135a-3p “hsa-mir-135a-1” (miRBase Accession No. MI000052, SEQ ID NO: 308) having a hairpin-like structure as a precursor is known.
- hsa-miR-8063 gene or “hsa-miR-8063” refers to the hsa-miR-8063 gene (miRBase Accession No. MIMAT0030990) described in SEQ ID NO: 58 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Wang HJ et al., 2013, Shock, 39, p480-487. As for “hsa-miR-8063”, “hsa-mir-8063” (miRBase Accession No. MI0025899, SEQ ID NO: 309) having a hairpin-like structure as a precursor is known.
- hsa-miR-5698 gene or “hsa-miR-5698” refers to the hsa-miR-5698 gene (miRBase Accession No. MIMAT0022491) described in SEQ ID NO: 59 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Watahiki A et al., 2011, PLoS One, Vol. 6, e24950. As for “hsa-miR-5698”, “hsa-mir-5698” (miRBase Accession No. MI0019305, SEQ ID NO: 310) having a hairpin-like structure as a precursor is known.
- hsa-miR-6089 gene or “hsa-miR-6089” refers to the hsa-miR-6089 gene (miRBase Accession No. MIMAT0023714) described in SEQ ID NO: 60 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Yoo JK et al., 2012, Stem Cells Dev, 21, p2049-2057. “Hsa-miR-6089” has a hairpin-like structure as a precursor thereof, “hsa-mir-6089-1, hsa-mir-6089-2” (miRBase Accession No. MI0020366, MI0023563, SEQ ID NO: 311 312) is known.
- hsa-miR-498 gene or “hsa-miR-498” refers to the hsa-miR-498 gene (miRBase Accession No. MIMAT0002824) described in SEQ ID NO: 61 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Bentwich I et al., 2005, Nat Genet, 37, p766-770. In addition, “hsa-miR-498” is known as “hsa-mir-498” (miRBase Accession No. MI0003142, SEQ ID NO: 313) having a hairpin-like structure as a precursor.
- hsa-miR-296-3p gene or “hsa-miR-296-3p” refer to the hsa-miR-296-3p gene described in SEQ ID NO: 62 (miRBase Accession No. MIMAT0004679) and other species homologs or orthologs.
- the gene can be obtained by the method described in Houbavy HB et al., 2003, Dev Cell, Vol. 5, p351-358.
- hsa-miR-296-3p is known as “hsa-mir-296” (miRBase Accession No. MI000047, SEQ ID NO: 314) having a hairpin-like structure as a precursor.
- hsa-miR-4419b gene or “hsa-miR-4419b” refers to the hsa-miR-4419b gene (miRBase Accession No. MIMAT0019034) described in SEQ ID NO: 63 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Also, “hsa-miR-4419b” is known as “hsa-mir-4419b” (miRBase Accession No. MI0016861, SEQ ID NO: 315) having a hairpin-like structure as a precursor.
- hsa-miR-6802-5p gene or “hsa-miR-6802-5p” refers to the hsa-miR-6802-5p gene described in SEQ ID NO: 64 (miRBase Accession No. MIMAT0027504) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6802-5p is known as “hsa-mir-6802” (miRBase Accession No. MI0022647, SEQ ID NO: 316) having a hairpin-like structure as a precursor.
- hsa-miR-6829-5p gene or “hsa-miR-6829-5p” refers to the hsa-miR-6829-5p gene described in SEQ ID NO: 65 (miRBase Accession No. MIMAT0027558) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6829-5p “hsa-mir-6829” (miRBase Accession No. MI0022674, SEQ ID NO: 317) having a hairpin-like structure as a precursor is known.
- hsa-miR-6803-5p gene or "hsa-miR-6803-5p” is, hsa-miR-6803-5p gene (miRBase Accession described in SEQ ID NO: 66 No. MIMAT0027506), etc. and other species homologs or orthologs are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6803-5p takes a hairpin-like structure "hsa-mir-6803" (miRBase Accession No.MI0022648, SEQ ID NO: 318) is known as its precursor.
- hsa-miR-1199-5p gene or “hsa-miR-1199-5p” refers to the hsa-miR-1199-5p gene (miRBase Accession No. MIMAT0031119) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Salvi A et al., 2013, Int J Oncol, 42, p391-402.
- hsa-miR-1199-5p is known as “hsa-mir-1199” (miRBase Accession No. MI0020340, SEQ ID NO: 319) having a hairpin-like structure as a precursor.
- hsa-miR-6840-3p gene or “hsa-miR-6840-3p” refers to the hsa-miR-6840-3p gene described in SEQ ID NO: 68 (miRBase Accession No. MIMAT0027583) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6840-3p “hsa-mir-6840” (miRBase Accession No. MI0022686, SEQ ID NO: 320) having a hairpin-like structure as a precursor is known.
- hsa-miR-6752-5p gene or “hsa-miR-6752-5p” refers to the hsa-miR-6752-5p gene described in SEQ ID NO: 69 (miRBase Accession No. MIMAT0027404) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “Hsa-miR-6752-5p” is known as “hsa-mir-6752” (miRBase Accession No. MI0022597, SEQ ID NO: 321) having a hairpin-like structure as a precursor.
- hsa-miR-6798-5p gene or “hsa-miR-6798-5p” refers to the hsa-miR-6798-5p gene described in SEQ ID NO: 70 (miRBase Accession No. MIMAT0027496) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6798-5p “hsa-mir-6798” (miRBase Accession No. MI0022643, SEQ ID NO: 322) having a hairpin-like structure as a precursor is known.
- hsa-miR-6131 gene or “hsa-miR-6131” refers to the hsa-miR-6131 gene (miRBase Accession No. MIMAT0024615) described in SEQ ID NO: 71 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Dannemann M et al., 2012, Genome Biol Evol, Vol. 4, p552-564. Also, “hsa-miR-6131” is known as “hsa-mir-6131” (miRBase Accession No. MI0021276, SEQ ID NO: 323) having a hairpin-like structure as a precursor.
- hsa-miR-4667-5p gene or “hsa-miR-4667-5p” refers to the hsa-miR-4667-5p gene described in SEQ ID NO: 72 (miRBase Accession No. MIMAT0019743) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4667-5p “hsa-mir-4667” (miRBase Accession No. MI0017297, SEQ ID NO: 324) having a hairpin-like structure as a precursor is known.
- hsa-miR-6510-5p gene or “hsa-miR-6510-5p” refers to the hsa-miR-6510-5p gene described in SEQ ID NO: 73 (miRBase Accession No. MIMAT0025476) and other species homologs or orthologs. The gene can be obtained by the method described in Joyce CE et al., 2011, Hum Mol Genet, 20, p4025-4040.
- “hsa-miR-6510-5p” is known as “hsa-mir-6510” (miRBase Accession No. MI0022222, SEQ ID NO: 325) having a hairpin-like structure as a precursor.
- hsa-miR-4690-5p gene or “hsa-miR-4690-5p” refers to the hsa-miR-4690-5p gene described in SEQ ID NO: 74 (miRBase Accession No. MIMAT0019779) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4690-5p “hsa-mir-4690” (miRBase Accession No. MI0017323, SEQ ID NO: 326) having a hairpin-like structure as a precursor is known.
- hsa-miR-920 gene or “hsa-miR-920” refers to the hsa-miR-920 gene (miRBase Accession No. MIMAT0004970) described in SEQ ID NO: 75 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Novotny GW et al., 2007, Int J Androl, 30, p316-326.
- hsa-miR-920 is known as “hsa-mir-920” (miRBase Accession No. MI0005712, SEQ ID NO: 327) having a hairpin-like structure as a precursor.
- hsa-miR-23b-3p gene or “hsa-miR-23b-3p” refers to the hsa-miR-23b-3p gene described in SEQ ID NO: 76 (miRBase Accession No. MIMAT000018) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Lagos-Quintana M et al., 2002, Curr Biol, 12, p735-739.
- hsa-miR-23b-3p “hsa-mir-23b” (miRBase Accession No. MI0000439, SEQ ID NO: 328) having a hairpin-like structure as a precursor is known.
- hsa-miR-4448 gene or “hsa-miR-4448” refers to the hsa-miR-4448 gene (miRBase Accession No. MIMAT0018967) described in SEQ ID NO: 77 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4448”, “hsa-mir-4448” (miRBase Accession No. MI0016791, SEQ ID NO: 329) having a hairpin-like structure as a precursor is known.
- hsa-miR-2110 gene or “hsa-miR-2110” refers to the hsa-miR-2110 gene (miRBase Accession No. MIMAT0010133) described in SEQ ID NO: 78 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Zhu JY et al., 2009, J Virol, 83, p3333-3341. As for “hsa-miR-2110”, “hsa-mir-2110” (miRBase Accession No. MI0010629, SEQ ID NO: 330) having a hairpin-like structure as a precursor is known.
- hsa-miR-4706 gene or “hsa-miR-4706” refers to the hsa-miR-4706 gene (miRBase Accession No. MIMAT0019806) described in SEQ ID NO: 79 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4706”, “hsa-mir-4706” (miRBase Accession No. MI0017339, SEQ ID NO: 331) having a hairpin-like structure as a precursor is known.
- hsa-miR-7845-5p gene or “hsa-miR-7845-5p” refers to the hsa-miR-7845-5p gene described in SEQ ID NO: 80 (miRBase Accession No. MIMAT0030420) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ple H et al., 2012, PLoS One, Vol. 7, e50746.
- hsa-miR-7845-5p “hsa-mir-7845” (miRBase Accession No. MI0025515, SEQ ID NO: 332) having a hairpin-like structure as a precursor is known.
- hsa-miR-6808-5p gene or “hsa-miR-6808-5p” refers to the hsa-miR-6808-5p gene described in SEQ ID NO: 81 (miRBase Accession No. 1). MIMAT0027516) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6808-5p “hsa-mir-6808” (miRBase Accession No. MI0022653, SEQ ID NO: 333) having a hairpin-like structure as a precursor is known.
- hsa-miR-4447 gene or “hsa-miR-4447” refers to the hsa-miR-4447 gene (miRBase Accession No. MIMAT0018966) described in SEQ ID NO: 82 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Further, “hsa-miR-4447” is known as “hsa-mir-4447” (miRBase Accession No. MI0016790, SEQ ID NO: 334), which has a hairpin-like structure as a precursor.
- hsa-miR-6869-5p gene or “hsa-miR-6869-5p” refers to the hsa-miR-6869-5p gene described in SEQ ID NO: 83 (miRBase Accession No. MIMAT0027638) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6869-5p “hsa-mir-6869” (miRBase Accession No. MI0022716, SEQ ID NO: 335) having a hairpin-like structure as a precursor is known.
- hsa-miR-1908-5p gene or “hsa-miR-1908-5p” refers to the hsa-miR-1908-5p gene described in SEQ ID NO: 84 (miRBase Accession No. MIMAT0007881) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Bar M et al., 2008, Stem Cells, 26, p2496-2505.
- “hsa-miR-1908-5p” is known as “hsa-mir-1908” (miRBase Accession No. MI0008329, SEQ ID NO: 336) having a hairpin-like structure as a precursor.
- hsa-miR-6729-5p gene or “hsa-miR-6729-5p” refers to the hsa-miR-6729-5p gene described in SEQ ID NO: 85 (miRBase Accession No. MIMAT0027359) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6729-5p “hsa-mir-6729” (miRBase Accession No. MI0022574, SEQ ID NO: 337) having a hairpin-like structure as a precursor is known.
- hsa-miR-5195-3p gene or “hsa-miR-5195-3p” refers to the hsa-miR-5195-3p gene described in SEQ ID NO: 86 (miRBase Accession No. MIMAT0021127) and other species homologs or orthologs are included.
- the gene can be obtained by the method described in Schotte D et al., 2011, Leukemia, 25, p1389-1399.
- hsa-miR-5195-3p “hsa-mir-5195” (miRBase Accession No. MI0018174, SEQ ID NO: 338) having a hairpin-like structure as a precursor is known.
- hsa-miR-638 gene or “hsa-miR-638” refers to the hsa-miR-638 gene (miRBase Accession No. MIMAT0003308) described in SEQ ID NO: 87 or other species. Homologs or orthologs are included. The gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692. As for “hsa-miR-638”, “hsa-mir-638” (miRBase Accession No. MI0003653, SEQ ID NO: 339) having a hairpin-like structure as a precursor is known.
- hsa-miR-6125 gene or “hsa-miR-6125” refers to the hsa-miR-6125 gene (miRBase Accession No. MIMAT0024598) described in SEQ ID NO: 88 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Smith JL et al., 2012, J Virol, 86, p5278-5287. As for “hsa-miR-6125”, “hsa-mir-6125” (miRBase Accession No. MI0021259, SEQ ID NO: 340) having a hairpin-like structure as a precursor is known.
- hsa-miR-3178 gene or “hsa-miR-3178” refers to the hsa-miR-3178 gene (miRBase Accession No. MIMAT0015055) described in SEQ ID NO: 89 or other species. Homologs or orthologs are included. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685. As for “hsa-miR-3178”, “hsa-mir-3178” (miRBase Accession No. MI0014212, SEQ ID NO: 341) having a hairpin-like structure as a precursor is known.
- hsa-miR-3196 gene or “hsa-miR-3196” refers to the hsa-miR-3196 gene (miRBase Accession No. MIMAT0015080) described in SEQ ID NO: 90 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685. As for “hsa-miR-3196”, “hsa-mir-3196” (miRBase Accession No. MI0014241, SEQ ID NO: 342) having a hairpin-like structure as a precursor is known.
- hsa-miR-8069 gene or “hsa-miR-8069” refers to the hsa-miR-8069 gene (miRBase Accession No. MIMAT0030996) described in SEQ ID NO: 91 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Wang HJ et al., 2013, Shock, 39, p480-487. “Hsa-miR-8069” has a hairpin-like structure as a precursor thereof, “hsa-mir-8069-1, hsa-mir-8069-2” (miRBase Accession No. MI0025905, MI0031519, SEQ ID NO: 343, 344) is known.
- hsa-miR-4723-5p gene or “hsa-miR-4723-5p” refers to the hsa-miR-4723-5p gene described in SEQ ID NO: 92 (miRBase Accession No. MIMAT0019838) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4723-5p “hsa-mir-4723” (miRBase Accession No. MI0017359, SEQ ID NO: 345) having a hairpin-like structure as a precursor is known.
- hsa-miR-4746-3p gene or “hsa-miR-4746-3p” refers to the hsa-miR-4746-3p gene described in SEQ ID NO: 93 (miRBase Accession No. MIMAT0019881) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4746-3p “hsa-mir-4746” (miRBase Accession No. MI0017385, SEQ ID NO: 346) having a hairpin-like structure as a precursor is known.
- hsa-miR-4689 gene or “hsa-miR-4689” refers to the hsa-miR-4689 gene (miRBase Accession No. MIMAT0019778) described in SEQ ID NO: 94 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4689”, “hsa-mir-4689” (miRBase Accession No. MI0017322, SEQ ID NO: 347) having a hairpin-like structure as a precursor is known.
- hsa-miR-6816-5p gene or “hsa-miR-6816-5p” refers to the hsa-miR-6816-5p gene described in SEQ ID NO: 95 (miRBase Accession No. MIMAT0027532) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6816-5p “hsa-mir-6816” (miRBase Accession No. MI0022661, SEQ ID NO: 348) having a hairpin-like structure as a precursor is known.
- hsa-miR-6757-5p gene or “hsa-miR-6757-5p” refers to the hsa-miR-6757-5p gene described in SEQ ID NO: 96 (miRBase Accession No. MIMAT0027414) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6757-5p” is known as “hsa-mir-6757” (miRBase Accession No. MI0022602, SEQ ID NO: 349) having a hairpin-like structure as a precursor.
- hsa-miR-7109-5p gene or “hsa-miR-7109-5p” refers to the hsa-miR-7109-5p gene described in SEQ ID NO: 97 (miRBase Accession No. MIMAT0028115) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-7109-5p” is known as “hsa-mir-7109” (miRBase Accession No. MI0022960, SEQ ID NO: 350) having a hairpin-like structure as a precursor.
- hsa-miR-6724-5p gene or “hsa-miR-6724-5p” refers to the hsa-miR-6724-5p gene described in SEQ ID NO: 98 (miRBase Accession No. MIMAT0025856) and other species homologs or orthologs.
- the gene can be obtained by the method described in Li Y et al., 2012, Gene, 497, p330-335.
- “Hsa-miR-6724-5p” has a hairpin-like structure as its precursor, “hsa-mir-6724-1, hsa-mir-6724-2, hsa-mir-6724-3, hsa-mir”.
- -6724-4 "(miRBBase Accession No. MI0022559, MI0031516, MI0031517, MI0031518, SEQ ID NOs: 351, 352, 353, and 354) are known.
- hsa-miR-1225-3p gene or “hsa-miR-1225-3p” refers to the hsa-miR-1225-3p gene described in SEQ ID NO: 99 (miRBase Accession No. MIMAT0005573) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336.
- hsa-miR-1225-3p is known as “hsa-mir-1225” (miRBase Accession No. MI0006311, SEQ ID NO: 355), which has a hairpin-like structure as a precursor.
- hsa-miR-6875-5p gene or “hsa-miR-6875-5p” refers to the hsa-miR-6875-5p gene described in SEQ ID NO: 100 (miRBase Accession No. MIMAT0027650) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6875-5p is known as “hsa-mir-6875” (miRBase Accession No. MI0022722, SEQ ID NO: 356) having a hairpin-like structure as a precursor.
- hsa-miR-7108-5p gene or “hsa-miR-7108-5p” refers to the hsa-miR-7108-5p gene described in SEQ ID NO: 101 (miRBase Accession No. MIMAT0028113) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-7108-5p is known as “hsa-mir-7108” (miRBase Accession No. MI0022959, SEQ ID NO: 357) having a hairpin-like structure as a precursor.
- hsa-miR-4508 gene or “hsa-miR-4508” refers to the hsa-miR-4508 gene (miRBase Accession No. MIMAT0019045) described in SEQ ID NO: 102 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4508”, “hsa-mir-4508” (miRBase Accession No. MI0016872, SEQ ID NO: 358) having a hairpin-like structure as a precursor is known.
- hsa-miR-6085 gene or “hsa-miR-6085” refers to the hsa-miR-6085 gene (miRBase Accession No. MIMAT0023710) described in SEQ ID NO: 103 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Voellenkle C et al., 2012, RNA, 18, p472-484. As for “hsa-miR-6085”, “hsa-mir-6085” (miRBase Accession No. MI0020362, SEQ ID NO: 359) having a hairpin-like structure as a precursor is known.
- hsa-miR-6679-5p gene or “hsa-miR-6779-5p” refers to the hsa-miR-6679-5p gene described in SEQ ID NO: 104 (miRBase Accession No. MIMAT0027458) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6779-5p” is known as “hsa-mir-6679” (miRBase Accession No. MI0022624, SEQ ID NO: 360) having a hairpin-like structure as a precursor.
- hsa-miR-642a-3p gene or “hsa-miR-642a-3p” refers to the hsa-miR-642a-3p gene described in SEQ ID NO: 105 (miRBase Accession No. MIMAT0020924) and other species homologs or orthologs.
- the gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692.
- “hsa-miR-642a-3p” is known as “hsa-mir-642a” (miRBase Accession No. MI0003657, SEQ ID NO: 361) having a hairpin-like structure as a precursor.
- hsa-miR-4695-5p gene or “hsa-miR-4695-5p” refers to the hsa-miR-4695-5p gene described in SEQ ID NO: 106 (miRBase Accession No. MIMAT0019788) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- “hsa-miR-4695-5p” is known as “hsa-mir-4695” (miRBase Accession No. MI0017328, SEQ ID NO: 362) having a hairpin-like structure as a precursor.
- hsa-miR-7847-3p gene or “hsa-miR-7847-3p” refers to the hsa-miR-7847-3p gene described in SEQ ID NO: 107 (miRBase Accession No. MIMAT0030422) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ple H et al., 2012, PLoS One, Vol. 7, e50746.
- hsa-miR-7847-3p is known as “hsa-mir-7847” (miRBase Accession No. MI0025517, SEQ ID NO: 363) having a hairpin-like structure as a precursor.
- hsa-miR-3197 gene or “hsa-miR-3197” refers to the hsa-miR-3197 gene (miRBase Accession No. MIMAT0015082) described in SEQ ID NO: 108 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685. As for “hsa-miR-3197”, “hsa-mir-3197” (miRBase Accession No. MI0014245, SEQ ID NO: 364) having a hairpin-like structure as a precursor is known.
- hsa-miR-6769b-5p gene or “hsa-miR-6769b-5p” refers to the hsa-miR-6769b-5p gene described in SEQ ID NO: 109 (miRBase Accession No. MIMAT0027620) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6769b-5p “hsa-mir-6769b” (miRBase Accession No. MI0022706, SEQ ID NO: 365) having a hairpin-like structure as a precursor is known.
- hsa-miR-7641 gene or “hsa-miR-7641” refers to the hsa-miR-7641 gene (miRBase Accession No. MIMAT0029782) described in SEQ ID NO: 110 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Yoo JK et al., 2013, Arch Pharm Res, 36, p353-358.
- “hsa-miR-7641” has a hairpin-like structure as a precursor thereof, “hsa-mir-7464-1, hsa-mir-7641-2” (miRBase Accession No. MI0024975, MI0024976, SEQ ID NO: 366, 367) is known.
- hsa-miR-187-5p gene or “hsa-miR-187-5p” refers to the hsa-miR-187-5p gene described in SEQ ID NO: 111 (miRBase Accession No. MIMAT0004561) and other species homologs or orthologs are included.
- the gene can be obtained by the method described in Lim LP et al., 2003, Science, 299, p1540.
- “hsa-miR-187-5p” is known as “hsa-mir-187” (miRBase Accession No. MI000000274, SEQ ID NO: 368) having a hairpin-like structure as a precursor.
- hsa-miR-3185 gene or “hsa-miR-3185” refers to the hsa-miR-3185 gene (miRBase Accession No. MIMAT0015065) described in SEQ ID NO: 112 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685. As for “hsa-miR-3185”, “hsa-mir-3185” (miRBase Accession No. MI0014227, SEQ ID NO: 369) having a hairpin-like structure as a precursor is known.
- hsa-miR-2861 gene or “hsa-miR-2861” refers to the hsa-miR-2861 gene (miRBase Accession No. MIMAT0013802) described in SEQ ID NO: 113 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Li H et al., 2009, J Clin Invest, 119, p3666-3777. As for “hsa-miR-2861”, “hsa-mir-2861” (miRBase Accession No. MI0013006, SEQ ID NO: 370) having a hairpin-like structure as a precursor is known.
- hsa-miR-3940-5p gene or “hsa-miR-3940-5p” refers to the hsa-miR-3940-5p gene described in SEQ ID NO: 114 (miRBase Accession No. MIMAT0019229) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Liao JY et al., 2010, PLoS One, Vol. 5, e10563.
- “hsa-miR-3940-5p” is known as “hsa-mir-3940” (miRBase Accession No. MI0016597, SEQ ID NO: 371) having a hairpin-like structure as a precursor.
- hsa-miR-1203 gene or “hsa-miR-1203” refers to the hsa-miR-1203 gene (miRBase Accession No. MIMAT0005866) described in SEQ ID NO: 115 or other species. Homologs or orthologs are included. The gene can be obtained by the method described in Marton S et al., 2008, Leukemia, Vol. 22, p330-338. “Hsa-miR-1203” is known as “hsa-mir-1203” (miRBase Accession No. MI0006335, SEQ ID NO: 372) having a hairpin-like structure as a precursor.
- hsa-miR-615-5p gene or “hsa-miR-615-5p” refers to the hsa-miR-615-5p gene described in SEQ ID NO: 116 (miRBase Accession No. MIMAT0004804) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692.
- “hsa-miR-615-5p” is known as “hsa-mir-615” (miRBase Accession No. MI0003628, SEQ ID NO: 373) having a hairpin-like structure as a precursor.
- hsa-miR-4787-5p gene or “hsa-miR-4787-5p” refers to the hsa-miR-4787-5p gene described in SEQ ID NO: 117 (miRBase Accession No. MIMAT0019956) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- “hsa-miR-4787-5p” is known as “hsa-mir-4787” (miRBase Accession No. MI0017434, SEQ ID NO: 374) having a hairpin-like structure as a precursor.
- hsa-miR-1343-3p gene or “hsa-miR-1343-3p” refers to the hsa-miR-1343-3p gene described in SEQ ID NO: 118 (miRBase Accession No. MIMAT0019776) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-1343-3p “hsa-mir-1343” (miRBase Accession No. MI0017320, SEQ ID NO: 375) having a hairpin-like structure as a precursor is known.
- hsa-miR-6813-5p gene or “hsa-miR-6813-5p” refers to the hsa-miR-6813-5p gene described in SEQ ID NO: 119 (miRBase Accession No. MIMAT0027526) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “Hsa-miR-6813-5p” is known as “hsa-mir-6683” (miRBase Accession No. MI0022658, SEQ ID NO: 376) having a hairpin-like structure as a precursor.
- hsa-miR-1225-5p gene or “hsa-miR-1225-5p” refers to the hsa-miR-1225-5p gene described in SEQ ID NO: 120 (miRBase Accession No. MIMAT0005572) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336.
- “Hsa-miR-1225-5p” is known as “hsa-mir-1225” (miRBase Accession No. MI0006311, SEQ ID NO: 377) having a hairpin-like structure as a precursor.
- hsa-miR-602 gene or “hsa-miR-602” refers to the hsa-miR-602 gene (miRBase Accession No. MIMAT0003270) described in SEQ ID NO: 121 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692. As for “hsa-miR-602”, “hsa-mir-602” (miRBase Accession No. MI0003615, SEQ ID NO: 378) having a hairpin-like structure as a precursor is known.
- hsa-miR-4488 gene or “hsa-miR-4488” refers to the hsa-miR-4488 gene (miRBase Accession No. MIMAT0019022) described in SEQ ID NO: 122 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Also, “hsa-miR-4488” is known as “hsa-mir-4488” (miRBase Accession No. MI0016849, SEQ ID NO: 379), which has a hairpin-like structure as a precursor.
- hsa-miR-125a-3p gene or “hsa-miR-125a-3p” refers to the hsa-miR-125a-3p gene described in SEQ ID NO: 123 (miRBase Accession No. MIMAT0004602) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Lagos-Quintana M et al., 2002, Curr Biol, 12, p735-739.
- “hsa-miR-125a-3p” is known as “hsa-mir-125a” (miRBase Accession No. MI000069, SEQ ID NO: 380) having a hairpin-like structure as a precursor.
- hsa-miR-5100 gene or “hsa-miR-5100” refers to the hsa-miR-5100 gene (miRBase Accession No. MIMAT0022259) described in SEQ ID NO: 124 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Tandon M et al., 2012, Oral Dis, Vol. 18, p127-131. As for “hsa-miR-5100”, “hsa-mir-5100” (miRBase Accession No. MI0019116, SEQ ID NO: 381) having a hairpin-like structure as a precursor is known.
- hsa-miR-4294 gene or “hsa-miR-4294” refers to the hsa-miR-4294 gene (miRBase Accession No. MIMAT0016849) described in SEQ ID NO: 125 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. Also, “hsa-miR-4294” is known as “hsa-mir-4294” (miRBase Accession No. MI0015827, SEQ ID NO: 382) having a hairpin-like structure as a precursor.
- hsa-miR-1231 gene or “hsa-miR-1231” refers to the hsa-miR-1231 gene (miRBase Accession No. MIMAT0005586) described in SEQ ID NO: 126 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336. Also, “hsa-miR-1231” is known as “hsa-mir-1231” (miRBase Accession No. MI0006321, SEQ ID NO: 383) having a hairpin-like structure as a precursor.
- hsa-miR-6765-3p gene or “hsa-miR-6765-3p” refers to the hsa-miR-6765-3p gene described in SEQ ID NO: 127 (miRBase Accession No. MIMAT0027431) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6765-3p “hsa-mir-6765” (miRBase Accession No. MI0022610, SEQ ID NO: 384) having a hairpin-like structure as a precursor is known.
- hsa-miR-4442 gene or “hsa-miR-4442” refers to the hsa-miR-4442 gene (miRBase Accession No. MIMAT0018960) described in SEQ ID NO: 128 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4442”, “hsa-mir-4442” (miRBase Accession No. MI0016785, SEQ ID NO: 385), which has a hairpin-like structure as a precursor, is known.
- hsa-miR-718 gene or “hsa-miR-718” refers to the hsa-miR-718 gene (miRBase Accession No. MIMAT0012735) described in SEQ ID NO: 129 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Artzi S et al., 2008, BMC Bioinformatics, Vol. 9, p39. In addition, “hsa-miR-718” is known as “hsa-mir-718” (miRBase Accession No. MI0012489, SEQ ID NO: 386) having a hairpin-like structure as a precursor.
- hsa-miR-6780b-5p gene or “hsa-miR-6780b-5p” refers to the hsa-miR-6780b-5p gene described in SEQ ID NO: 130 (miRBase Accession No. MIMAT0027572) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6780b-5p “hsa-mir-6780b” (miRBase Accession No. MI0022681, SEQ ID NO: 387) having a hairpin-like structure as a precursor is known.
- hsa-miR-6090 gene or “hsa-miR-6090” refers to the hsa-miR-6090 gene (miRBase Accession No. MIMAT0023715) described in SEQ ID NO: 131 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Yoo JK et al., 2012, Stem Cells Dev, 21, p2049-2057. Further, “hsa-miR-6090” is known as “hsa-mir-6090” (miRBase Accession No. MI0020367, SEQ ID NO: 388) having a hairpin-like structure as a precursor.
- hsa-miR-6845-5p gene or “hsa-miR-6845-5p” refers to the hsa-miR-6845-5p gene described in SEQ ID NO: 132 (miRBase Accession No. MIMAT0027590) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6845-5p “hsa-mir-6845” (miRBase Accession No. MI0022691, SEQ ID NO: 389) having a hairpin-like structure as a precursor is known.
- hsa-miR-4741 gene or “hsa-miR-4741” refers to the hsa-miR-4741 gene (miRBase Accession No. MIMAT0019871) described in SEQ ID NO: 133 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4741 is known as “hsa-mir-4741” (miRBase Accession No. MI0017379, SEQ ID NO: 390) having a hairpin-like structure as a precursor.
- hsa-miR-4467 gene or “hsa-miR-4467” refers to the hsa-miR-4467 gene (miRBase Accession No. MIMAT0018994) described in SEQ ID NO: 134 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Further, “hsa-miR-4467” is known as “hsa-mir-4467” (miRBase Accession No. MI0016818, SEQ ID NO: 391) having a hairpin-like structure as a precursor.
- hsa-miR-4707-5p gene or “hsa-miR-4707-5p” refers to the hsa-miR-4707-5p gene (miRBase Accession No. MIMAT0019807) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- “hsa-miR-4707-5p” is known as “hsa-mir-4707” (miRBase Accession No. MI0017340, SEQ ID NO: 392) having a hairpin-like structure as a precursor.
- hsa-miR-4271 gene or “hsa-miR-4271” refers to the hsa-miR-4271 gene (miRBase Accession No. MIMAT0016901) described in SEQ ID NO: 136 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. As for “hsa-miR-4271”, “hsa-mir-4271” (miRBase Accession No. MI0015879, SEQ ID NO: 393) having a hairpin-like structure as a precursor is known.
- hsa-miR-4673 gene or “hsa-miR-4673” refers to the hsa-miR-4673 gene (miRBase Accession No. MIMAT0019755) described in SEQ ID NO: 137 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4673”, “hsa-mir-4673” (miRBase Accession No. MI0017304, SEQ ID NO: 394) having a hairpin-like structure as a precursor is known.
- hsa-miR-3184-5p gene or “hsa-miR-3184-5p” refers to the hsa-miR-3184-5p gene described in SEQ ID NO: 138 (miRBase Accession No. MIMAT0015064) and other species homologs or orthologs.
- the gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685.
- hsa-miR-3184-5p “hsa-mir-3184” (miRBase Accession No. MI0014226, SEQ ID NO: 395) having a hairpin-like structure as a precursor is known.
- hsa-miR-1469 gene or “hsa-miR-1469” refers to the hsa-miR-1469 gene (miRBase Accession No. MIMAT0007347) described in SEQ ID NO: 139 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Kawaji H et al., 2008, BMC Genomics, Vol. 9, p157. “Hsa-miR-1469” is known to have “hsa-mir-1469” (miRBase Accession No. MI00000074, SEQ ID NO: 396) having a hairpin-like structure as a precursor.
- hsa-miR-4640-5p gene or “hsa-miR-4640-5p” refers to the hsa-miR-4640-5p gene described in SEQ ID NO: 140 (miRBase Accession No. MIMAT0019699) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4640-5p “hsa-mir-4640” (miRBase Accession No. MI0017267, SEQ ID NO: 397) having a hairpin-like structure as a precursor is known.
- hsa-miR-663a gene or “hsa-miR-663a” refers to the hsa-miR-663a gene (miRBase Accession No. MIMAT0003326) described in SEQ ID NO: 141 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692. As for “hsa-miR-663a”, “hsa-mir-663a” (miRBase Accession No. MI0003672, SEQ ID NO: 398) having a hairpin-like structure as a precursor is known.
- hsa-miR-6791-5p gene or “hsa-miR-6791-5p” refers to the hsa-miR-6791-5p gene described in SEQ ID NO: 142 (miRBase Accession No. MIMAT0027482) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6791-5p” is known as “hsa-mir-6791” (miRBase Accession No. MI0022636, SEQ ID NO: 399) having a hairpin-like structure as a precursor.
- hsa-miR-6826-5p gene or “hsa-miR-6826-5p” refers to the hsa-miR-6826-5p gene described in SEQ ID NO: 143 (miRBase Accession No. MIMAT0027552) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6826-5p “hsa-mir-6826” (miRBase Accession No. MI0022671, SEQ ID NO: 400) having a hairpin-like structure as a precursor is known.
- hsa-miR-4433b-3p gene or “hsa-miR-4433b-3p” refers to the hsa-miR-4433b-3p gene described in SEQ ID NO: 144 (miRBase Accession No. MIMAT0030414) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ple H et al., 2012, PLoS One, Vol. 7, e50746.
- hsa-miR-4433b-3p is known as “hsa-mir-4433b” (miRBase Accession No. MI0025511, SEQ ID NO: 401) having a hairpin-like structure as a precursor.
- hsa-miR-1915-3p gene or “hsa-miR-1915-3p” refers to the hsa-miR-1915-3p gene described in SEQ ID NO: 145 (miRBase Accession No. MIMAT0007892) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Bar M et al., 2008, Stem Cells, 26, p2496-2505.
- hsa-miR-1915-3p “hsa-mir-1915” (miRBase Accession No. MI0008336, SEQ ID NO: 402) having a hairpin-like structure as a precursor is known.
- hsa-miR-4417 gene or “hsa-miR-4417” refers to the hsa-miR-4417 gene (miRBase Accession No. MIMAT0018929) described in SEQ ID NO: 146 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4417”, “hsa-mir-4417” (miRBase Accession No. MI0016753, SEQ ID NO: 403) having a hairpin-like structure as a precursor is known.
- hsa-miR-4449 gene or “hsa-miR-4449” refers to the hsa-miR-4449 gene (miRBase Accession No. MIMAT0018968) described in SEQ ID NO: 147 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Also, “hsa-miR-4449” is known as “hsa-mir-4449” (miRBase Accession No. MI0016792, SEQ ID NO: 404) having a hairpin-like structure as a precursor.
- hsa-miR-4707-3p gene or “hsa-miR-4707-3p” refers to the hsa-miR-4707-3p gene described in SEQ ID NO: 148 (miRBase Accession No. MIMAT0019808) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4707-3p “hsa-mir-4707” (miRBase Accession No. MI0017340, SEQ ID NO: 405) having a hairpin-like structure as a precursor is known.
- hsa-miR-3180-3p gene or “hsa-miR-3180-3p” refers to the hsa-miR-3180-3p gene described in SEQ ID NO: 149 (miRBase Accession No. MIMAT0015058) and other species homologs or orthologs.
- the gene can be obtained by the method described in Creighton CJ et al., 2010, PLoS One, 5, e9637.
- “hsa-miR-3180-3p” has a hairpin-like structure as its precursor, “hsa-mir-3180-1, hsa-mir-3180-2, hsa-mir-3180-3” (miRBBase Accession No. MI0014214, MI0014215, MI0014217, SEQ ID NOs: 406, 407, and 408) are known.
- hsa-miR-5585-3p gene or “hsa-miR-5585-3p” refers to the hsa-miR-5585-3p gene described in SEQ ID NO: 150 (miRBase Accession No. MIMAT0022286) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Friedlander MR et al., 2012, Nucleic Acids Res, 40, p37-52.
- hsa-miR-5585-3p “hsa-mir-5585” (miRBase Accession No. MI0019142, SEQ ID NO: 409) having a hairpin-like structure as a precursor is known.
- hsa-miR-1268a gene or “hsa-miR-1268a” refers to the hsa-miR-1268a gene (miRBase Accession No. MIMAT0005922) described in SEQ ID NO: 151 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Morin RD et al., 2008, Genome Res, 18, p610-621. As for “hsa-miR-1268a”, “hsa-mir-1268a” (miRBase Accession No. MI0006405, SEQ ID NO: 410) having a hairpin-like structure as a precursor is known.
- hsa-miR-8072 gene or “hsa-miR-8072” refers to the hsa-miR-8072 gene (miRBase Accession No. MIMAT0030999) described in SEQ ID NO: 152 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Wang HJ et al., 2013, Shock, 39, p480-487. As for “hsa-miR-8072”, “hsa-mir-8072” (miRBase Accession No. MI0025908, SEQ ID NO: 411) having a hairpin-like structure as a precursor is known.
- hsa-miR-296-5p gene or “hsa-miR-296-5p” refers to the hsa-miR-296-5p gene described in SEQ ID NO: 153 (miRBase Accession No. MIMAT060690) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Houbavy HB et al., 2003, Dev Cell, Vol. 5, p351-358.
- hsa-miR-296-5p is known as “hsa-mir-296” (miRBase Accession No. MI000047, SEQ ID NO: 412), which has a hairpin-like structure as a precursor.
- hsa-miR-204-3p gene or “hsa-miR-204-3p” refers to the hsa-miR-204-3p gene described in SEQ ID NO: 154 (miRBase Accession No. MIMAT0022693) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Lim LP et al., 2003, Science, 299, p1540.
- hsa-miR-204-3p “hsa-mir-204” (miRBase Accession No. MI00000028, SEQ ID NO: 413) having a hairpin-like structure as a precursor is known.
- hsa-miR-4454 gene or “hsa-miR-4454” refers to the hsa-miR-4454 gene (miRBase Accession No. MIMAT0018976) described in SEQ ID NO: 155 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4454”, “hsa-mir-4454” (miRBase Accession No. MI0016800, SEQ ID NO: 414) having a hairpin-like structure as a precursor is known.
- hsa-miR-6722-3p gene or “hsa-miR-6722-3p” refers to the hsa-miR-6722-3p gene described in SEQ ID NO: 156 (miRBase Accession No. MIMAT0025854) and other species homologs or orthologs are included.
- the gene can be obtained by the method described in Li Y et al., 2012, Gene, 497, p330-335.
- hsa-miR-6722-3p “hsa-mir-6722” (miRBase Accession No. MI0022557, SEQ ID NO: 415) having a hairpin-like structure as a precursor is known.
- hsa-miR-1290 gene or “hsa-miR-1290” refers to the hsa-miR-1290 gene (miRBase Accession No. MIMAT0005880) described in SEQ ID NO: 157 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Morin RD et al., 2008, Genome Res, 18, p610-621. As for “hsa-miR-1290”, “hsa-mir-1290” (miRBase Accession No. MI0006352, SEQ ID NO: 416) having a hairpin-like structure as a precursor is known.
- hsa-miR-3622a-5p gene or “hsa-miR-3622a-5p” refers to the hsa-miR-3622a-5p gene described in SEQ ID NO: 158 (miRBase Accession No. MIMAT0018003) and other species homologs or orthologs.
- the gene can be obtained by the method described in Witten D et al., 2010, BMC Biol, Vol. 8, p58.
- hsa-mir-3622a miRBase Accession No. MI0016013, SEQ ID NO: 417) having a hairpin-like structure as a precursor is known.
- hsa-miR-939-5p gene or “hsa-miR-939-5p” refers to the hsa-miR-939-5p gene described in SEQ ID NO: 159 (miRBase Accession No. MIMAT0004982) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Lui WO et al., 2007, Cancer Res, Vol. 67, p6031-6043.
- “hsa-miR-939-5p” is known as “hsa-mir-939” (miRBase Accession No. MI0005761, SEQ ID NO: 418) having a hairpin-like structure as a precursor.
- hsa-miR-675-5p gene or “hsa-miR-675-5p” refers to the hsa-miR-675-5p gene described in SEQ ID NO: 160 (miRBase Accession No. MIMAT0004284) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Cai X et al., 2007, RNA, Vol. 13, p313-316.
- hsa-miR-675-5p “hsa-mir-675” (miRBase Accession No. MI0005416, SEQ ID NO: 419) having a hairpin-like structure as a precursor is known.
- hsa-miR-3131 gene or “hsa-miR-3131” refers to the hsa-miR-3131 gene (miRBase Accession No. MIMAT0014996) described in SEQ ID NO: 161 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685. Also, “hsa-miR-3131” is known as “hsa-mir-3131” (miRBase Accession No. MI0014151, SEQ ID NO: 420) having a hairpin-like structure as a precursor.
- hsa-miR-4648 gene or “hsa-miR-4648” refers to the hsa-miR-4648 gene (miRBase Accession No. MIMAT0019710) described in SEQ ID NO: 162 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4648 is known as “hsa-mir-4648” (miRBase Accession No. MI0017275, SEQ ID NO: 421) having a hairpin-like structure as a precursor.
- hsa-miR-1268b gene or “hsa-miR-1268b” refers to the hsa-miR-1268b gene (miRBase Accession No. MIMAT0018925) described in SEQ ID NO: 163 or other species. A homolog or ortholog is included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Also, “hsa-miR-1268b” is known as “hsa-mir-1268b” (miRBase Accession No. MI0016748, SEQ ID NO: 422) having a hairpin-like structure as a precursor.
- hsa-miR-6741-5p gene or “hsa-miR-6741-5p” refers to the hsa-miR-6741-5p gene (miRBase Accession No. MIMAT0027383) and other species homologs or orthologs are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6741-5p is known as “hsa-mir-6741” (miRBase Accession No. MI0022586, SEQ ID NO: 423) having a hairpin-like structure as a precursor.
- hsa-miR-6893-5p gene or “hsa-miR-6893-5p” refers to the hsa-miR-6893-5p gene described in SEQ ID NO: 165 (miRBase Accession No. MIMAT0027686) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6893-5p “hsa-mir-6893” (miRBase Accession No. MI0022740, SEQ ID NO: 424) having a hairpin-like structure as a precursor is known.
- hsa-miR-3162-5p gene or “hsa-miR-3162-5p” refers to the hsa-miR-3162-5p gene described in SEQ ID NO: 166 (miRBase Accession No. MIMAT0015036) and other species homologs or orthologs. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685.
- hsa-miR-3162-5p is known as “hsa-mir-3162” (miRBase Accession No. MI0014192, SEQ ID NO: 425) having a hairpin-like structure as a precursor.
- hsa-miR-642b-3p gene or “hsa-miR-642b-3p” refers to the hsa-miR-642b-3p gene described in SEQ ID NO: 167 (miRBase Accession No. MIMAT0018444) and other species homologs or orthologs. The gene can be obtained by the method described in Witten D et al., 2010, BMC Biol, Vol. 8, p58.
- hsa-miR-642b-3p is known as “hsa-mir-642b” (miRBase Accession No. MI0016685, SEQ ID NO: 426) having a hairpin-like structure as a precursor.
- hsa-miR-4734 gene or “hsa-miR-4734” refers to the hsa-miR-4734 gene (miRBase Accession No. MIMAT0019859) described in SEQ ID NO: 168 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4734”, “hsa-mir-4734” (miRBase Accession No. MI0017371, SEQ ID NO: 427) having a hairpin-like structure as a precursor is known.
- hsa-miR-150-3p gene or “hsa-miR-150-3p” refers to the hsa-miR-150-3p gene described in SEQ ID NO: 169 (miRBase Accession No. MIMAT0004610) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Lagos-Quintana M et al., 2002, Curr Biol, 12, p735-739.
- “hsa-miR-150-3p” is known as “hsa-mir-150” (miRBase Accession No. MI0000479, SEQ ID NO: 428) having a hairpin-like structure as a precursor.
- hsa-miR-8089 gene or “hsa-miR-8089” refers to the hsa-miR-8089 gene (miRBase Accession No. MIMAT0031016) described in SEQ ID NO: 170 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Wang HJ et al., 2013, Shock, 39, p480-487.
- hsa-miR-8089 is known as “hsa-mir-8089” (miRBase Accession No. MI0025925, SEQ ID NO: 429) having a hairpin-like structure as a precursor.
- hsa-miR-6805-3p gene or “hsa-miR-6805-3p” refers to the hsa-miR-6805-3p gene described in SEQ ID NO: 171 (miRBase Accession No. MIMAT0027511) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6805-3p” is known as “hsa-mir-6805” (miRBase Accession No. MI0022650, SEQ ID NO: 430) having a hairpin-like structure as a precursor.
- hsa-miR-7113-3p gene or “hsa-miR-7113-3p” refers to the hsa-miR-7113-3p gene described in SEQ ID NO: 172 (miRBase Accession No. MIMAT0028124) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-7113-3p is known as “hsa-mir-7113” (miRBase Accession No. MI0022964, SEQ ID NO: 431) having a hairpin-like structure as a precursor.
- hsa-miR-6850-5p gene or “hsa-miR-6850-5p” refers to the hsa-miR-6850-5p gene described in SEQ ID NO: 173 (miRBase Accession No. MIMAT0027600) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-mir-6850 miRBase Accession No. MI0022696, SEQ ID NO: 432 having a hairpin-like structure as a precursor is known.
- hsa-miR-6799-5p gene or “hsa-miR-6799-5p” refers to the hsa-miR-6799-5p gene described in SEQ ID NO: 174 (miRBase Accession No. MIMAT0027498) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6799-5p “hsa-mir-6799” (miRBase Accession No. MI0022644, SEQ ID NO: 433) having a hairpin-like structure as a precursor is known.
- hsa-miR-6768-5p gene or “hsa-miR-6768-5p” refers to the hsa-miR-6768-5p gene described in SEQ ID NO: 175 (miRBase Accession No. MIMAT0027436) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6768-5p “hsa-mir-6768” (miRBase Accession No. MI0022613, SEQ ID NO: 434) having a hairpin-like structure as a precursor is known.
- hsa-miR-92b-5p gene or “hsa-miR-92b-5p” refers to the hsa-miR-92b-5p gene described in SEQ ID NO: 176 (miRBase Accession No. MIMAT0004792) and other species homologs or orthologs are included.
- the gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692.
- hsa-miR-92b-5p “hsa-mir-92b” (miRBase Accession No. MI0003560, SEQ ID NO: 435) having a hairpin-like structure as a precursor is known.
- hsa-miR-3679-5p gene or “hsa-miR-3679-5p” refers to the hsa-miR-3679-5p gene described in SEQ ID NO: 177 (miRBase Accession No. MIMAT0018104) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Creighton CJ et al., 2010, PLoS One, 5, e9637.
- hsa-miR-3679-5p is known as “hsa-mir-3679” (miRBase Accession No. MI0016080, SEQ ID NO: 436) having a hairpin-like structure as a precursor.
- hsa-miR-4792 gene or “hsa-miR-4792” refers to the hsa-miR-4792 gene (miRBase Accession No. MIMAT0019964) described in SEQ ID NO: 178 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4792”, “hsa-mir-4792” (miRBase Accession No. MI0017439, SEQ ID NO: 437) having a hairpin-like structure as a precursor is known.
- hsa-miR-3656 gene or “hsa-miR-3656” refers to the hsa-miR-3656 gene (miRBase Accession No. MIMAT0018076) described in SEQ ID NO: 179 or other species. Homologs or orthologs are included. The gene can be obtained by the method described in Meiri E et al., 2010, Nucleic Acids Res, 38, p6234-6246.
- hsa-miR-3656 is known as “hsa-mir-3656” (miRBase Accession No. MI0016056, SEQ ID NO: 438) having a hairpin-like structure as a precursor.
- hsa-miR-92a-2-5p gene or “hsa-miR-92a-2-5p” refers to the hsa-miR-92a-2-5p set forth in SEQ ID NO: 180.
- Genes (miRBase Accession No. MIMAT0004508) and other species homologues or orthologues are included. The gene can be obtained by the method described in Mourelatos Z et al., 2002, Genes Dev, 16, p 720-728.
- hsa-miR-92a-2-5p is known as “hsa-mir-92a-2” (miRBase Accession No. MI00000094, SEQ ID NO: 439) having a hairpin-like structure as a precursor.
- hsa-miR-4466 gene or “hsa-miR-4466” refers to the hsa-miR-4466 gene (miRBase Accession No. MIMAT0018993) described in SEQ ID NO: 181 and other biological species. A homolog or ortholog is included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4466”, “hsa-mir-4466” (miRBase Accession No. MI0016817, SEQ ID NO: 440) having a hairpin-like structure as a precursor is known.
- hsa-miR-4513 gene or “hsa-miR-4513” refers to the hsa-miR-4513 gene (miRBase Accession No. MIMAT0019050) described in SEQ ID NO: 182 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4513”, “hsa-mir-4513” (miRBase Accession No. MI0016879, SEQ ID NO: 441) having a hairpin-like structure as a precursor is known.
- hsa-miR-6781-5p gene or “hsa-miR-6781-5p” refers to the hsa-miR-6781-5p gene described in SEQ ID NO: 183 (miRBase Accession No. MIMAT0027462) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6781-5p” is known as “hsa-mir-6781” (miRBase Accession No. MI0022626, SEQ ID NO: 442) having a hairpin-like structure as a precursor.
- hsa-miR-4649-5p gene or “hsa-miR-4649-5p” refers to the hsa-miR-4649-5p gene described in SEQ ID NO: 184 (miRBase Accession No. MIMAT0019711) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4649-5p “hsa-mir-4649” (miRBase Accession No. MI0017276, SEQ ID NO: 443) having a hairpin-like structure as a precursor is known.
- hsa-miR-6775-5p gene or “hsa-miR-6775-5p” refers to the hsa-miR-6775-5p gene described in SEQ ID NO: 185 (miRBase Accession No. MIMAT0027450) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6775-5p is known as “hsa-mir-6775” (miRBase Accession No. MI0022620, SEQ ID NO: 444) having a hairpin-like structure as a precursor.
- hsa-miR-4651 gene or “hsa-miR-4651” refers to the hsa-miR-4651 gene (miRBase Accession No. MIMAT0019715) described in SEQ ID NO: 186 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. Also, “hsa-miR-4651” is known as “hsa-mir-4651” (miRBase Accession No. MI0017279, SEQ ID NO: 445) having a hairpin-like structure as a precursor.
- hsa-miR-3195 gene or “hsa-miR-3195” refers to the hsa-miR-3195 gene (miRBase Accession No. MIMAT0015079) described in SEQ ID NO: 187 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685. As for “hsa-miR-3195”, “hsa-mir-3195” (miRBase Accession No. MI0014240, SEQ ID NO: 446) having a hairpin-like structure as a precursor is known.
- hsa-miR-6726-5p gene or “hsa-miR-6726-5p” refers to the hsa-miR-6726-5p gene described in SEQ ID NO: 188 (miRBase Accession No. MIMAT0027353) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6726-5p “hsa-mir-6726” (miRBase Accession No. MI0022571, SEQ ID NO: 447) having a hairpin-like structure as a precursor is known.
- hsa-miR-6872-3p gene or “hsa-miR-6872-3p” refers to the hsa-miR-6872-3p gene described in SEQ ID NO: 189 (miRBase Accession No. MIMAT0027645) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6872-3p is known as “hsa-mir-6872” (miRBase Accession No. MI0022719, SEQ ID NO: 448) having a hairpin-like structure as a precursor.
- hsa-miR-371a-5p gene or “hsa-miR-371a-5p” refers to the hsa-miR-371a-5p gene described in SEQ ID NO: 190 (miRBase Accession No. MIMAT0004687) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Suh MR et al., 2004, Dev Biol, 270, p488-498.
- hsa-miR-371a-5p “hsa-mir-371a” (miRBase Accession No. MI000079, SEQ ID NO: 449) having a hairpin-like structure as a precursor is known.
- hsa-miR-6777-5p gene or “hsa-miR-6777-5p” refers to the hsa-miR-6777-5p gene described in SEQ ID NO: 191 (miRBase Accession No. MIMAT0027454) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6777-5p “hsa-mir-6777” (miRBase Accession No. MI0022622, SEQ ID NO: 450) having a hairpin-like structure as a precursor is known.
- hsa-miR-6789-5p gene or “hsa-miR-6789-5p” refers to the hsa-miR-6789-5p gene described in SEQ ID NO: 192 (miRBase Accession No. MIMAT0027478) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6789-5p “hsa-mir-6789” (miRBase Accession No. MI0022634, SEQ ID NO: 451) having a hairpin-like structure as a precursor is known.
- hsa-miR-7975 gene or “hsa-miR-7975” refers to the hsa-miR-7975 gene (miRBase Accession No. MIMAT0031178) described in SEQ ID NO: 193 or other biological species. A homolog or ortholog is included. The gene can be obtained by the method described in Velthut-Meikas A, et al., 2013, Endocrinol, 27, p1128-1141. Also, “hsa-miR-7975” is known as “hsa-mir-7975” (miRBase Accession No. MI0025751, SEQ ID NO: 452) having a hairpin-like structure as a precursor.
- hsa-miR-6821-5p gene or “hsa-miR-6821-5p” refers to the hsa-miR-6821-5p gene described in SEQ ID NO: 194 (miRBase Accession No. MIMAT0027542) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6821-5p” is known as “hsa-mir-6682” (miRBase Accession No. MI0022666, SEQ ID NO: 453) having a hairpin-like structure as a precursor.
- hsa-miR-4534 gene or “hsa-miR-4534” refers to the hsa-miR-4534 gene (miRBase Accession No. MIMAT0019073) described in SEQ ID NO: 195 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. “Hsa-miR-4534” is known as “hsa-mir-4534” (miRBase Accession No. MI0016901, SEQ ID NO: 454) having a hairpin-like structure as a precursor.
- hsa-miR-619-5p gene or “hsa-miR-619-5p” refers to the hsa-miR-619-5p gene described in SEQ ID NO: 196 (miRBase Accession No. MIMAT0026622) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Cummins JM et al., 2006, Proc Natl Acad Sci US A, 103, p3687-3692.
- “hsa-miR-619-5p” is known as “hsa-mir-619” (miRBase Accession No. MI0003633, SEQ ID NO: 455) having a hairpin-like structure as a precursor.
- hsa-miR-7107-5p gene or “hsa-miR-7107-5p” refers to the hsa-miR-7107-5p gene (miRBase Accession No. MIMAT0028111) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-mir-7107 miRBase Accession No. MI0022958, SEQ ID NO: 456 having a hairpin-like structure as a precursor is known.
- hsa-miR-1228-3p gene or “hsa-miR-1228-3p” refers to the hsa-miR-1228-3p gene (miRBase Accession No. MIMAT0005583) and other species homologs or orthologs.
- the gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336.
- hsa-miR-1228-3p “hsa-mir-1228” (miRBase Accession No. MI0006318, SEQ ID NO: 457) having a hairpin-like structure as a precursor is known.
- hsa-miR-6774-5p gene or “hsa-miR-6774-5p” refers to the hsa-miR-6774-5p gene described in SEQ ID NO: 199 (miRBase Accession No. MIMAT0027448) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6774-5p “hsa-mir-6774” (miRBase Accession No. MI0022619, SEQ ID NO: 458) having a hairpin-like structure as a precursor is known.
- hsa-miR-6805-5p gene or “hsa-miR-6805-5p” refers to the hsa-miR-6805-5p gene described in SEQ ID NO: 200 (miRBase Accession No. MIMAT0027510) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6805-5p is known as “hsa-mir-6805” (miRBase Accession No. MI0022650, SEQ ID NO: 459), which has a hairpin-like structure as a precursor.
- hsa-miR-23a-3p gene or “hsa-miR-23a-3p” refers to the hsa-miR-23a-3p gene (miRBase Accession No. MIMAT0000078) and other species homologs or orthologs.
- the gene can be obtained by the method described in Lagos-Quintana M et al., 2001, Science, 294, p853-858.
- hsa-miR-23a-3p “hsa-mir-23a” (miRBase Accession No. MI0000079, SEQ ID NO: 460) having a hairpin-like structure as a precursor is known.
- hsa-miR-4665-5p gene or “hsa-miR-4665-5p” refers to the hsa-miR-4665-5p gene (miRBase Accession No. MIMAT0019739) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- “hsa-miR-4665-5p” “hsa-mir-4665” (miRBase Accession No. MI0017295, SEQ ID NO: 461) having a hairpin-like structure as a precursor is known.
- hsa-miR-4505 gene or “hsa-miR-4505” refers to the hsa-miR-4505 gene (miRBase Accession No. MIMAT0019041) described in SEQ ID NO: 203 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Also, “hsa-miR-4505” is known as “hsa-mir-4505” (miRBase Accession No. MI0016868, SEQ ID NO: 462) having a hairpin-like structure as a precursor.
- hsa-miR-4638-5p gene or “hsa-miR-4638-5p” refers to the hsa-miR-4638-5p gene described in SEQ ID NO: 204 (miRBase Accession No. MIMAT0019695) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4638-5p “hsa-mir-4638” (miRBase Accession No. MI0017265, SEQ ID NO: 463) having a hairpin-like structure as a precursor is known.
- hsa-miR-24-3p gene or “hsa-miR-24-3p” refers to the hsa-miR-24-3p gene described in SEQ ID NO: 205 (miRBase Accession No. MIMAT00000080) and other species homologs or orthologs.
- the gene can be obtained by the method described in Lagos-Quintana M et al., 2001, Science, 294, p853-858.
- “Hsa-miR-24-3p” has a hairpin-like structure as a precursor thereof, “hsa-mir-24-1, hsa-mir-24-2” (miRBBase Accession No. MI00000080, MI00000081, SEQ ID NO: 464, 465) are known.
- hsa-miR-3135b gene or “hsa-miR-3135b” refers to the hsa-miR-3135b gene (miRBase Accession No. MIMAT0018985) described in SEQ ID NO: 206 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. “Hsa-miR-3135b” is known as “hsa-mir-3135b” (miRBase Accession No. MI0016809, SEQ ID NO: 466) having a hairpin-like structure as a precursor.
- hsa-miR-4745-5p gene or “hsa-miR-4745-5p” refers to the hsa-miR-4745-5p gene described in SEQ ID NO: 207 (miRBase Accession No. MIMAT0019878) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4745-5p “hsa-mir-4745” (miRBase Accession No. MI0017384, SEQ ID NO: 467) having a hairpin-like structure as a precursor is known.
- hsa-miR-128-1-5p gene or “hsa-miR-128-1-5p” refers to the hsa-miR-128-1-5p set forth in SEQ ID NO: 208.
- Genes (miRBBase Accession No. MIMAT0026477) and other species homologues or orthologues are included. The gene can be obtained by the method described in Lagos-Quintana M et al., 2002, Curr Biol, 12, p735-739.
- hsa-miR-128-1-5p “hsa-mir-128-1” (miRBase Accession No. MI0000447, SEQ ID NO: 468) having a hairpin-like structure as a precursor is known.
- hsa-miR-4476 gene or “hsa-miR-4476” refers to the hsa-miR-4476 gene (miRBase Accession No. MIMAT0019003) described in SEQ ID NO: 209 or other biological species. A homolog or ortholog is included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4476”, “hsa-mir-4476” (miRBase Accession No. MI0016828, SEQ ID NO: 469) having a hairpin-like structure as a precursor is known.
- hsa-miR-4687-3p gene or “hsa-miR-4687-3p” refers to the hsa-miR-4687-3p gene described in SEQ ID NO: 210 (miRBase Accession No. MIMAT0019775) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4687-3p “hsa-mir-4687” (miRBase Accession No. MI0017319, SEQ ID NO: 470) having a hairpin-like structure as a precursor is known.
- hsa-miR-3665 gene or “hsa-miR-3665” refers to the hsa-miR-3665 gene (miRBase Accession No. MIMAT0018087) described in SEQ ID NO: 211 and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Xie X et al., 2005, Nature, 434, p338-345.
- hsa-miR-3665 is known as “hsa-mir-3665” (miRBase Accession No. MI0016066, SEQ ID NO: 471) having a hairpin-like structure as a precursor.
- hsa-miR-6806-5p gene or “hsa-miR-6806-5p” refers to the hsa-miR-6806-5p gene described in SEQ ID NO: 212 (miRBase Accession No. MIMAT0027512) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6806-5p” is known as “hsa-mir-6806” (miRBase Accession No. MI0022651, SEQ ID NO: 472) having a hairpin-like structure as a precursor.
- hsa-miR-3937 gene or “hsa-miR-3937” refers to the hsa-miR-3937 gene (miRBase Accession No. MIMAT0018352) described in SEQ ID NO: 213 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Liao JY et al., 2010, PLoS One, Vol. 5, e10563. As for “hsa-miR-3937”, “hsa-mir-3937” (miRBase Accession No. MI0016593, SEQ ID NO: 473) having a hairpin-like structure as a precursor is known.
- hsa-miR-711 gene or “hsa-miR-711” refers to the hsa-miR-711 gene (miRBase Accession No. MIMAT0012734) described in SEQ ID NO: 214 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Artzi S et al., 2008, BMC Bioinformatics, Vol. 9, p39. In addition, “hsa-miR-711” is known as “hsa-mir-711” (miRBase Accession No. MI0012488, SEQ ID NO: 474) having a hairpin-like structure as a precursor.
- hsa-miR-3141 gene or “hsa-miR-3141” refers to the hsa-miR-3141 gene (miRBase Accession No. MIMAT0015010) described in SEQ ID NO: 215 or other biological species. A homolog or ortholog is included. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685. Also, “hsa-miR-3141” is known as “hsa-mir-3141” (miRBase Accession No. MI0014165, SEQ ID NO: 475) having a hairpin-like structure as a precursor.
- hsa-miR-3188 gene or “hsa-miR-3188” refers to the hsa-miR-3188 gene (miRBase Accession No. MIMAT0015070) described in SEQ ID NO: 216 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685. As for “hsa-miR-3188”, “hsa-mir-3188” (miRBase Accession No. MI0014232, SEQ ID NO: 476) having a hairpin-like structure as a precursor is known.
- hsa-miR-4281 gene or “hsa-miR-4281” refers to the hsa-miR-4281 gene (miRBase Accession No. MIMAT0016907) described in SEQ ID NO: 217 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. As for “hsa-miR-4281”, “hsa-mir-4281” (miRBase Accession No. MI0015885, SEQ ID NO: 477) having a hairpin-like structure as a precursor is known.
- hsa-miR-5196-5p gene or “hsa-miR-5196-5p” refers to the hsa-miR-5196-5p gene described in SEQ ID NO: 218 (miRBase Accession No. MIMAT0021128) and other species homologs or orthologs. The gene can be obtained by the method described in Schotte D et al., 2011, Leukemia, 25, p1389-1399.
- hsa-miR-5196-5p “hsa-mir-5196” (miRBase Accession No. MI0018175, SEQ ID NO: 478) having a hairpin-like structure as a precursor is known.
- hsa-miR-6880-5p gene or “hsa-miR-6880-5p” refers to the hsa-miR-6880-5p gene described in SEQ ID NO: 219 (miRBase Accession No. MIMAT0027660) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6880-5p “hsa-mir-6880” (miRBase Accession No. MI0022727, SEQ ID NO: 479) having a hairpin-like structure as a precursor is known.
- hsa-miR-3960 gene or “hsa-miR-3960” refers to the hsa-miR-3960 gene (miRBase Accession No. MIMAT0019337) described in SEQ ID NO: 220 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Hu R et al., 2011, J Biol Chem, 286, p12328-12339. As for “hsa-miR-3960”, “hsa-mir-3960” (miRBase Accession No. MI0016964, SEQ ID NO: 480) having a hairpin-like structure as a precursor is known.
- hsa-miR-3648 gene or “hsa-miR-3648” refers to the hsa-miR-3648 gene (miRBase Accession No. MIMAT0018068) described in SEQ ID NO: 221, and other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Meiri E et al., 2010, Nucleic Acids Res, 38, p6234-6246. “Hsa-miR-3648” has a hairpin-like structure as a precursor thereof, “hsa-mir-3648-1, hsa-mir-3648-2” (miRBase Accession No. MI0016048, MI0031512, SEQ ID NO: 481, 482) is known.
- hsa-miR-6721-5p gene or “hsa-miR-6721-5p” refers to the hsa-miR-6721-5p gene described in SEQ ID NO: 222 (miRBase Accession No. MIMAT0025852) and other species homologs or orthologs.
- the gene can be obtained by the method described in Li Y et al., 2012, Gene, 497, p330-335.
- hsa-miR-6721-5p “hsa-mir-6721” (miRBase Accession No. MI0022556, SEQ ID NO: 483) having a hairpin-like structure as a precursor is known.
- hsa-miR-4492 gene or “hsa-miR-4492” refers to the hsa-miR-4492 gene (miRBase Accession No. MIMAT0019027) described in SEQ ID NO: 223 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Also, “hsa-miR-4492” is known as “hsa-mir-4492” (miRBase Accession No. MI0016854, SEQ ID NO: 484) having a hairpin-like structure as a precursor.
- hsa-miR-744-5p gene or “hsa-miR-744-5p” refers to the hsa-miR-744-5p gene described in SEQ ID NO: 224 (miRBase Accession No. MIMAT0004945) and other species homologs or orthologs.
- the gene can be obtained by the method described in Berezikov E et al., 2006, Genome Res, 16, p1289-1298.
- hsa-miR-744-5p is known as “hsa-mir-744” (miRBase Accession No. MI0005559, SEQ ID NO: 485), which has a hairpin-like structure as a precursor.
- hsa-miR-7704 gene or “hsa-miR-7704” refers to the hsa-miR-7704 gene (miRBase Accession No. MIMAT0030019) described in SEQ ID NO: 225 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Swamithan S et al., 2013, Biochem Biophys Res Commun, 434, p228-234. As for “hsa-miR-7704”, “hsa-mir-7704” (miRBase Accession No. MI0025240, SEQ ID NO: 486) having a hairpin-like structure as a precursor is known.
- hsa-miR-4749-5p gene or “hsa-miR-4749-5p” refers to the hsa-miR-4749-5p gene described in SEQ ID NO: 226 (miRBase Accession No. MIMAT0019885) and other species homologs or orthologs.
- the gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4749-5p “hsa-mir-4749” (miRBase Accession No. MI0017388, SEQ ID NO: 487) having a hairpin-like structure as a precursor is known.
- hsa-miR-6794-5p gene or “hsa-miR-6794-5p” refers to the hsa-miR-6794-5p gene described in SEQ ID NO: 227 (miRBase Accession No. MIMAT0027488) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6794-5p “hsa-mir-6794” (miRBase Accession No. MI0022639, SEQ ID NO: 488) having a hairpin-like structure as a precursor is known.
- hsa-miR-6511a-5p gene or “hsa-miR-6511a-5p” refers to the hsa-miR-6511a-5p gene described in SEQ ID NO: 228 (miRBase Accession No. MIMAT0025478) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Joyce CE et al., 2011, Hum Mol Genet, 20, p4025-4040.
- “Hsa-miR-6511a-5p” has a hairpin-like structure as its precursor, “hsa-mir-6651a-1, hsa-mir-6651a-2, hsa-mir-6651a-3, hsa-mir”.
- -6511a-4 "(miRBase Accession No. MI0022223, MI0023564, MI0023565, MI0023566, SEQ ID NOs: 489, 490, 491, 492) are known.
- hsa-miR-6824-5p gene or “hsa-miR-6824-5p” refers to the hsa-miR-6824-5p gene described in SEQ ID NO: 229 (miRBase Accession No. MIMAT0027548) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6824-5p “hsa-mir-6824” (miRBase Accession No. MI0022669, SEQ ID NO: 493) having a hairpin-like structure as a precursor is known.
- hsa-miR-762 gene or “hsa-miR-762” refers to the hsa-miR-762 gene (miRBase Accession No. MIMAT0010313) described in SEQ ID NO: 230 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Berezikov E et al., 2006, Genome Res, 16, p1289-1298. As for “hsa-miR-762”, “hsa-mir-762” (miRBase Accession No. MI0003892, SEQ ID NO: 494) having a hairpin-like structure as a precursor is known.
- hsa-miR-6836-3p gene or “hsa-miR-6836-3p” refers to the hsa-miR-6683-3p gene (miRBase Accession No. 231 described in SEQ ID NO: 231). MIMAT0027575) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6836-3p “hsa-mir-6836” (miRBase Accession No. MI0022682, SEQ ID NO: 495) having a hairpin-like structure as a precursor is known.
- hsa-miR-6727-5p gene or “hsa-miR-6727-5p” refers to the hsa-miR-6727-5p gene described in SEQ ID NO: 232 (miRBase Accession No. MIMAT0027355) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6727-5p “hsa-mir-6727” (miRBase Accession No. MI0022572, SEQ ID NO: 496) having a hairpin-like structure as a precursor is known.
- hsa-miR-4739 gene or “hsa-miR-4739” refers to the hsa-miR-4739 gene (miRBase Accession No. MIMAT0019868) described in SEQ ID NO: 233 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4739”, “hsa-mir-4739” (miRBase Accession No. MI0017377, SEQ ID NO: 497) having a hairpin-like structure as a precursor is known.
- hsa-miR-7777 gene or “hsa-miR-7777” refers to the hsa-miR-7777 gene (miRBase Accession No. MIMAT0031180) described in SEQ ID NO: 234 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Velthut-Meikas A, et al., 2013, Endocrinol, 27, p1128-1141. As for “hsa-miR-7777”, “hsa-mir-7777” (miRBase Accession No. MI0025753, SEQ ID NO: 498) having a hairpin-like structure as a precursor is known.
- hsa-miR-4484 gene or “hsa-miR-4484” refers to the hsa-miR-4484 gene (miRBase Accession No. MIMAT0019018) described in SEQ ID NO: 235 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. “Hsa-miR-4484” is known as “hsa-mir-4484” (miRBase Accession No. MI0016845, SEQ ID NO: 499) having a hairpin-like structure as a precursor.
- hsa-miR-6515-3p gene or “hsa-miR-6515-3p” refers to the hsa-miR-6515-3p gene described in SEQ ID NO: 236 (miRBase Accession No. MIMAT0025487) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Joyce CE et al., 2011, Hum Mol Genet, 20, p4025-4040.
- hsa-mir-6515 (miRBase Accession No. MI0022227, SEQ ID NO: 500) having a hairpin-like structure as a precursor is known.
- hsa-miR-373-5p gene or “hsa-miR-373-5p” refers to the hsa-miR-373-5p gene described in SEQ ID NO: 237 (miRBase Accession No. MIMAT000025) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Suh MR et al., 2004, Dev Biol, 270, p488-498.
- hsa-miR-373-5p “hsa-mir-373” (miRBase Accession No. MI0000811, SEQ ID NO: 501) having a hairpin-like structure as a precursor is known.
- hsa-miR-4258 gene or “hsa-miR-4258” refers to the hsa-miR-4258 gene (miRBase Accession No. MIMAT0016879) described in SEQ ID NO: 238 or other biological species. A homolog or ortholog is included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. Also, “hsa-miR-4258” is known as “hsa-mir-4258” (miRBase Accession No. MI0015857, SEQ ID NO: 502) having a hairpin-like structure as a precursor.
- hsa-miR-4675 gene or “hsa-miR-4675” refers to the hsa-miR-4675 gene (miRBase Accession No. MIMAT0019756) described in SEQ ID NO: 239 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4675”, “hsa-mir-4675” (miRBase Accession No. MI0017305, SEQ ID NO: 503) having a hairpin-like structure as a precursor is known.
- hsa-miR-3180 gene or “hsa-miR-3180” refers to the hsa-miR-3180 gene (miRBase Accession No. MIMAT0018178) described in SEQ ID NO: 240 and other species. Homologs or orthologs are included. The gene can be obtained by the method described in Creighton CJ et al., 2010, PLoS One, 5, e9637. “Hsa-miR-3180” has a hairpin-like structure as a precursor thereof, “hsa-mir-3180-4, hsa-mir-3180-5” (miRBBase Accession No. MI0016408, MI0016409, SEQ ID NO: 504 505) is known.
- hsa-miR-6076 gene or “hsa-miR-6076” refers to the hsa-miR-6076 gene (miRBase Accession No. MIMAT0023701) described in SEQ ID NO: 241 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Voellenkle C et al., 2012, RNA, 18, p472-484. As for “hsa-miR-6076”, “hsa-mir-6076” (miRBase Accession No. MI0020353, SEQ ID NO: 506) having a hairpin-like structure as a precursor is known.
- hsa-miR-1238-5p gene or “hsa-miR-1238-5p” refers to the hsa-miR-1238-5p gene (miRBase Accession No. MIMAT0022947) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Berezikov E et al., 2007, Mol Cell, 28, p328-336.
- hsa-miR-1238-5p is known as “hsa-mir-1238” (miRBase Accession No. MI0006328, SEQ ID NO: 507) having a hairpin-like structure as a precursor.
- hsa-miR-4463 gene or “hsa-miR-4463” refers to the hsa-miR-4463 gene (miRBase Accession No. MIMAT0018987) described in SEQ ID NO: 243 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. Further, “hsa-miR-4463” is known as “hsa-mir-4463” (miRBase Accession No. MI0016811, SEQ ID NO: 508) having a hairpin-like structure as a precursor.
- hsa-miR-4486 gene or “hsa-miR-4486” refers to the hsa-miR-4486 gene (miRBase Accession No. MIMAT0019020) described in SEQ ID NO: 244 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Jim DD et al., 2010, Blood, 116, e118-e127. As for “hsa-miR-4486”, “hsa-mir-4486” (miRBase Accession No. MI0016847, SEQ ID NO: 509) having a hairpin-like structure as a precursor is known.
- hsa-miR-4730 gene or “hsa-miR-4730” refers to the hsa-miR-4730 gene (miRBase Accession No. MIMAT0019852) described in SEQ ID NO: 245 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86.
- hsa-miR-4730 is known as “hsa-mir-4730” (miRBase Accession No. MI0017367, SEQ ID NO: 510) having a hairpin-like structure as a precursor.
- hsa-miR-6766-3p gene or “hsa-miR-6766-3p” refers to the hsa-miR-6766-3p gene described in SEQ ID NO: 246 (miRBase Accession No. MIMAT0027433) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- hsa-miR-6766-3p “hsa-mir-6766” (miRBase Accession No. MI0022611, SEQ ID NO: 511) having a hairpin-like structure as a precursor is known.
- hsa-miR-4286 gene or “hsa-miR-4286” refers to the hsa-miR-4286 gene (miRBase Accession No. MIMAT0016916) described in SEQ ID NO: 247 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Goff LA et al., 2009, PLoS One, Vol. 4, e7192. As for “hsa-miR-4286”, “hsa-mir-4286” (miRBase Accession No. MI0015894, SEQ ID NO: 512) having a hairpin-like structure as a precursor is known.
- hsa-miR-6511a-5p gene or “hsa-miR-6511a-5p” refers to the hsa-miR-6511a-5p gene described in SEQ ID NO: 248 (miRBase Accession No. MIMAT0025478) and other species homologues or orthologues are included.
- the gene can be obtained by the method described in Joyce CE et al., 2011, Hum Mol Genet, 20, p4025-4040.
- “Hsa-miR-6511a-5p” has a hairpin-like structure as its precursor, “hsa-mir-6651a-1, hsa-mir-6651a-2, hsa-mir-6651a-3, hsa-mir”.
- -6511a-4 "(miRBase Accession No. MI0022223, MI0023564, MI0023565, MI0023566, SEQ ID NO: 513, 514, 515, 516) is known.
- hsa-miR-4739 gene or “hsa-miR-4739” refers to the hsa-miR-4739 gene (miRBase Accession No. MIMAT0019868) described in SEQ ID NO: 249 or other biological species. Homologs or orthologs are included. The gene can be obtained by the method described in Personson H et al., 2011, Cancer Res, 71, p78-86. As for “hsa-miR-4739”, “hsa-mir-4739” (miRBase Accession No. MI0017377, SEQ ID NO: 517) having a hairpin-like structure as a precursor is known.
- hsa-miR-6749-5p gene or “hsa-miR-6749-5p” refers to the hsa-miR-6749-5p gene described in SEQ ID NO: 250 (miRBase Accession No. MIMAT0027398) and other species homologs or orthologs.
- the gene can be obtained by the method described in Ladewig E et al., 2012, Genome Res, Vol. 22, p1634-1645.
- “hsa-miR-6749-5p” is known as “hsa-mir-6749” (miRBase Accession No. MI0022594, SEQ ID NO: 518) having a hairpin-like structure as a precursor.
- a mature miRNA when cleaved as a mature miRNA from an RNA precursor having a hairpin-like structure, one to several bases before and after the sequence may be cleaved or long, or base substitution may occur.
- the resulting mutant may be called isomiR (Morin RD. Et al., 2008, Genome Res., Vol. 18, p.610-621).
- miRBBase Release 20 in addition to the nucleotide sequence represented by any of SEQ ID NOs: 1 to 250, various variants and fragments of the nucleotide sequence represented by any of SEQ ID NOs: 519 to 812 called isomiR are also shown. Yes.
- These mutants can also be obtained as miRNA having the base sequence represented by any of SEQ ID NOs: 1 to 250. That is, SEQ ID NOs: 2, 3, 6, 7, 8, 11, 12, 13, 15, 19, 20, 25, 26, 27, 29, 31, 32, 37, 44, 45, 46, 47 of the present invention.
- nucleic acid probe or primer used in the present invention binds to a specific target nucleic acid and cannot substantially bind to another nucleic acid.
- the present invention makes it possible to easily and accurately detect early pancreatic cancer or pancreatic cancer precursor lesions.
- pancreatic cancer or pancreatic cancer precursor lesions easily using the measured value of several miRNA expression levels in blood, serum and / or plasma of patients that can be collected minimally invasively Can be detected.
- This figure shows hsa-miR-1343-3p represented by SEQ ID NO: 118 generated from hsa-mir-1343 represented by SEQ ID NO: 264, and hsa-miR represented by SEQ ID NO: 14.
- the left figure of FIG. 2 shows hsa-miR of pancreatic cancer precursor lesion patients (21), early pancreatic cancer patients (31), and healthy subjects (123) selected as a learning sample group (training cohort).
- a discriminant is created from the measured expression level of ⁇ 6784-5p (SEQ ID NO: 1) using Fisher's discriminant analysis (3.10 ⁇ hsa-miR-miR-6784-5p-39.85).
- the discrimination score obtained from (1) is represented on the vertical axis, and the sample group is represented on the horizontal axis.
- the dotted line in the figure indicates a discrimination boundary for discriminating both groups having a discrimination score of 0.
- the right diagram of FIG. 2 shows hsa- in pancreatic cancer precursor lesion patients (12), early pancreatic cancer patients (13), and healthy subjects (61) selected as a validation sample group.
- the expression level measurement value of miR-6784-5p represents the discriminant score obtained from the discriminant created in the learning sample group as the vertical axis and the sample group as the horizontal axis. .
- the dotted line in the figure indicates a discrimination boundary for discriminating both groups having a discrimination score of 0.
- FIG. 3 shows hsa-miR-6784 in pancreatic cancer precursor lesion patients (21), early pancreatic cancer patients (31), and healthy subjects (123) selected as a learning sample group.
- a discriminant was created from the measured expression levels of 5p (SEQ ID NO: 1) and hsa-miR-1181 (SEQ ID NO: 2) using Fisher's discriminant analysis (1.90 ⁇ hsa-miR-6784-5p + 1.72 ⁇ hsa-miR-1181-34.50), the discriminant score obtained from the discriminant is represented on the vertical axis, and the sample group is represented on the horizontal axis.
- the dotted line in the figure indicates a discrimination boundary for discriminating both groups having a discrimination score of 0.
- FIG. 3 shows hsa-miR-6784 in pancreatic cancer precursor lesion patients (12), early pancreatic cancer patients (13), and healthy subjects (61) selected as the verification sample group.
- the discrimination score obtained from the discriminant created in the learning sample group is the vertical axis, and the sample group is It is expressed as an axis.
- the dotted line in the figure indicates a discrimination boundary for discriminating both groups having a discrimination score of 0.
- pancreatic cancer precursor lesions selected as a learning sample group 31 patients with early pancreatic cancer, 128 healthy bodies, 61 patients with advanced pancreatic cancer, 66 patients with biliary tract cancer, 51 breast cancer patients, 35 prostate cancer patients, 31 colon cancer patients, 32 stomach cancer patients, 34 esophageal cancer patients, 38 liver cancer patients, 15 pancreatic benign disease patients, and prostate benign disease Hsa-miR-4695-5p (SEQ ID NO: 106), hsa-miR-5090 (SEQ ID NO: 12), hsa-miR-4673 (SEQ ID NO: 137), hsa-miR-6913-5p (SEQ ID NO: 119) of 26 patients ), A discriminant was created from the measured expression level of hsa-miR-642a-3p (SEQ ID NO: 105) using Fisher's discriminant analysis (0.48 ⁇ hsa-miR-4695-5p-1.75 ⁇ h).
- the discriminant score obtained from the discriminant Is the vertical axis and the sample group is the horizontal axis.
- the dotted line in the figure indicates a discrimination boundary for discriminating both groups having a discrimination score of 0.
- the lower diagram in FIG. 4 shows 12 patients with pancreatic cancer precursor lesions, 13 patients with early pancreatic cancer, 56 healthy subjects, 39 patients with advanced pancreatic cancer, 32 patients with biliary tract cancer, and breast cancer.
- the discriminant score obtained from the discriminant created in the learning sample group is represented on the vertical axis and the sample group is represented on the horizontal axis for the expression level measurement value of ⁇ 3p (SEQ ID NO: 105).
- the dotted line in the figure indicates a discrimination boundary for discriminating both groups having a discrimination score of 0.
- target nucleic acid for early pancreatic cancer or pancreatic cancer precursor lesions Using the nucleic acid probe or primer for detection of early pancreatic cancer or pancreatic cancer precursor lesions as defined above of the present invention, early pancreatic cancer or pancreatic cancer precursor
- Primary target nucleic acids as early pancreatic cancer or pancreatic cancer precursor lesion markers for detecting the presence or absence of lesions or early pancreatic cancer or pancreatic cancer precursor lesion cells include hsa-miR- 6784-5p, hsa-miR-1181, hsa-miR-671-5p, hsa-miR-6857-5p, hsa-miR-4276, hsa-miR-1914-3p, hsa-miR-149-3p, hsa- miR-937-5p, hsa-miR-4675, hsa-miR-6695-5p, hsa-m
- pancreatic cancer or pancreatic cancer precursor lesion markers that can be combined with these miRNAs: hsa-miR-1908-5p, hsa-miR-6729-5p, hsa-miR-5195-3p, hsa -MiR-638, hsa-miR-6125, hsa-miR-3178, hsa-miR-3196, hsa-miR-8069, hsa-miR-4723-5p, hsa-miR-4746-3p, hsa-miR-4689 Hsa-miR-6816-5p, hsa-miR-6757-5p, hsa-miR-7109-5p, hsa-miR-6724-5p, hsa-miR-1225-3p, hsa-miR-6875-5p, hsa -MiR-7108-5p
- the miRNA includes, for example, a human gene containing a nucleotide sequence represented by any of SEQ ID NOs: 1 to 250 (ie, hsa-miR-6784-5p, hsa-miR-1181, hsa-miR-671, respectively).
- a preferred target nucleic acid is a human gene comprising the nucleotide sequence represented by any of SEQ ID NOs: 1 to 812, its transcription product, more preferably the transcription product, ie, miRNA, its precursor RNA, pri-miRNA or pre- miRNA.
- the first target gene is the hsa-miR-6784-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the second target gene is the hsa-miR-1181 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the third target gene is the hsa-miR-671-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the fourth target gene is the hsa-miR-6857-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the fifth target gene is the hsa-miR-4276 gene, their homologs, their transcripts, or their mutants or derivatives. Until now, there has been no report that changes in the expression of genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the sixth target gene is the hsa-miR-1914-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the seventh target gene is the hsa-miR-149-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the eighth target gene is the hsa-miR-937-5p gene, their homologues, their transcription products, or their mutants or derivatives. Until now, there has been no report that changes in the expression of genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the ninth target gene is the hsa-miR-4675 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the tenth target gene is the hsa-miR-6695-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the eleventh target gene is the hsa-miR-4731-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the twelfth target gene is the hsa-miR-5090 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the thirteenth target gene is the hsa-miR-3620-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the fourteenth target gene is the hsa-miR-1343-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the fifteenth target gene is the hsa-miR-6717-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 16th target gene is the hsa-miR-6825-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 17th target gene is the hsa-miR-6738-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 18th target gene is the hsa-miR-6769a-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the nineteenth target gene is the hsa-miR-4728-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the twentieth target gene is the hsa-miR-652-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 21st target gene is the hsa-miR-4257 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 22nd target gene is the hsa-miR-6785-5p gene, their homologues, their transcripts, or their mutants or derivatives. Until now, there has been no report that changes in the expression of genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 23rd target gene is the hsa-miR-7110-5p gene, their homologues, their transcripts, or their mutants or derivatives. Until now, there has been no report that changes in the expression of genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 24th target gene is the hsa-miR-6687-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 25th target gene is the hsa-miR-887-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 26th target gene is the hsa-miR-1228-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 27th target gene is the hsa-miR-5572 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 28th target gene is the hsa-miR-6782-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 29th target gene is the hsa-miR-4298 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 30th target gene is the hsa-miR-6786-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the thirty-first target gene is the hsa-miR-5010-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the thirty-second target gene is the hsa-miR-6087 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 33rd target gene is the hsa-miR-6765-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 34th target gene is the hsa-miR-6732-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 35th target gene is the hsa-miR-6787-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the thirty-sixth target gene is the hsa-miR-6737-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 37th target gene is an hsa-miR-128-2-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 38th target gene is the hsa-miR-4270 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 39th target gene is the hsa-miR-6861-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 40th target gene is the hsa-miR-6756-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 41st target gene is the hsa-miR-1229-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the forty-second target gene is the hsa-miR-6891-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 43rd target gene is the hsa-miR-6848-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 44th target gene is the hsa-miR-1237-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 45th target gene is the hsa-miR-30c-1-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 46th target gene is the hsa-miR-1233-5p gene, their homologues, their transcription products, or their mutants or derivatives. Until now, there has been no report that changes in the expression of genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 47th target gene is the hsa-miR-211-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 48th target gene is the hsa-miR-4758-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 49th target gene is an hsa-miR-614 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 50th target gene is the hsa-miR-6746-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 51st target gene is the hsa-miR-1915-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 52nd target gene is the hsa-miR-4688 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 53rd target gene is the hsa-miR-3917 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 54th target gene is the hsa-miR-5787 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 55th target gene is the hsa-miR-4632-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 56th target gene is the hsa-miR-6126 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 57th target gene is the hsa-miR-135a-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 58th target gene is the hsa-miR-8063 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 59th target gene is the hsa-miR-5698 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 60th target gene is the hsa-miR-6089 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 61st target gene is the hsa-miR-498 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 62nd target gene is the hsa-miR-296-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 63rd target gene is the hsa-miR-4419b gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 64th target gene is the hsa-miR-6802-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 65th target gene is the hsa-miR-6829-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 66th target gene is the hsa-miR-6803-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 67th target gene is the hsa-miR-1199-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 68th target gene is the hsa-miR-6840-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 69th target gene is the hsa-miR-6675-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 70th target gene is the hsa-miR-6798-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 71st target gene is an hsa-miR-6131 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 72nd target gene is the hsa-miR-4667-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 73rd target gene is the hsa-miR-6510-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 74th target gene is an hsa-miR-4690-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 75th target gene is the hsa-miR-920 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 76th target gene is an hsa-miR-23b-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 77th target gene is the hsa-miR-4448 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 78th target gene is the hsa-miR-2110 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 79th target gene is the hsa-miR-4706 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- genes or transcripts thereof can be markers for early pancreatic cancer or pancreatic cancer precursor lesions.
- the 80th target gene is the hsa-miR-7845-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 81st target gene is the hsa-miR-6808-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 82nd target gene is the hsa-miR-4447 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 83rd target gene is the hsa-miR-6869-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 84th target gene is the hsa-miR-1908-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 85th target gene is the hsa-miR-6729-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 86th target gene is the hsa-miR-5195-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 87th target gene is an hsa-miR-638 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 88th target gene is the hsa-miR-6125 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 89th target gene is the hsa-miR-3178 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 90th target gene is the hsa-miR-3196 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 91st target gene is the hsa-miR-8069 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 92nd target gene is the hsa-miR-4723-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 93rd target gene is the hsa-miR-4746-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 94th target gene is the hsa-miR-4687 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 95th target gene is the hsa-miR-6816-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 96th target gene is the hsa-miR-6757-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 97th target gene is the hsa-miR-7109-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 98th target gene is the hsa-miR-6724-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 99th target gene is the hsa-miR-1225-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 100th target gene is the hsa-miR-6875-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 101st target gene is the hsa-miR-7108-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 102nd target gene is the hsa-miR-4508 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 103rd target gene is the hsa-miR-6085 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 104th target gene is the hsa-miR-6679-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 105th target gene is an hsa-miR-642a-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 106th target gene is the hsa-miR-4695-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 107th target gene is the hsa-miR-7847-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 108th target gene is the hsa-miR-3197 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 109th target gene is the hsa-miR-6769b-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 110th target gene is the hsa-miR-7641 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 111th target gene is the hsa-miR-187-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 112th target gene is the hsa-miR-3185 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 113th target gene is the hsa-miR-2861 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 114th target gene is an hsa-miR-3940-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 115th target gene is the hsa-miR-1203 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 116th target gene is the hsa-miR-615-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 117th target gene is the hsa-miR-4787-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 118th target gene is the hsa-miR-1343-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 119th target gene is the hsa-miR-6813-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 120th target gene is the hsa-miR-1225-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 121st target gene is an hsa-miR-602 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 122nd target gene is the hsa-miR-4488 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 123rd target gene is the hsa-miR-125a-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 124th target gene is the hsa-miR-5100 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 125th target gene is the hsa-miR-4294 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 126th target gene is the hsa-miR-1231 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 127th target gene is the hsa-miR-6765-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 128th target gene is the hsa-miR-4442 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 129th target gene is the hsa-miR-718 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 130th target gene is the hsa-miR-6780b-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 131st target gene is an hsa-miR-6090 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 132nd target gene is the hsa-miR-6845-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 133rd target gene is the hsa-miR-4741 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 134th target gene is the hsa-miR-4467 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 135th target gene is the hsa-miR-4707-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 136th target gene is the hsa-miR-4271 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 137th target gene is the hsa-miR-4673 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 138th target gene is the hsa-miR-3184-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 139th target gene is the hsa-miR-1469 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 140th target gene is the hsa-miR-4640-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Non-Patent Document 5).
- the 141st target gene is the hsa-miR-663a gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 142nd target gene is the hsa-miR-6791-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the target gene 143 is the hsa-miR-6826-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 144th target gene is the hsa-miR-4433b-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 145th target gene is the hsa-miR-1915-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 146th target gene is the hsa-miR-4417 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 147th target gene is the hsa-miR-4449 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 148th target gene is the hsa-miR-4707-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 149th target gene is the hsa-miR-3180-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 150th target gene is the hsa-miR-5585-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 151st target gene is the hsa-miR-1268a gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for early pancreatic cancer or pancreatic cancer precursor lesions Patent Document 4.
- the 152th target gene is the hsa-miR-8072 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 153rd target gene is the hsa-miR-296-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for early pancreatic cancer or pancreatic cancer precursor lesions Patent Document 5.
- the 154th target gene is the hsa-miR-204-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 155th target gene is the hsa-miR-4454 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 156th target gene is the hsa-miR-6722-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 157th target gene is an hsa-miR-1290 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 158th target gene is the hsa-miR-3622a-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 159th target gene is an hsa-miR-939-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for early pancreatic cancer or pancreatic cancer precursor lesions Patent Document 4.
- the 160th target gene is the hsa-miR-675-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 161st target gene is the hsa-miR-3131 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 162nd target gene is the hsa-miR-4648 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 163rd target gene is the hsa-miR-1268b gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 164th target gene is the hsa-miR-6741-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 165th target gene is the hsa-miR-6893-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 166th target gene is the hsa-miR-3162-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 167th target gene is the hsa-miR-642b-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for early pancreatic cancer or pancreatic cancer precursor lesions Patent Document 4.
- the 168th target gene is the hsa-miR-4734 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 169th target gene is an hsa-miR-150-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 170th target gene is the hsa-miR-8089 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 171st target gene is the hsa-miR-6805-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 172nd target gene is the hsa-miR-7113-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 173rd target gene is the hsa-miR-6850-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 174th target gene is the hsa-miR-6799-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 175th target gene is the hsa-miR-6768-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 176th target gene is the hsa-miR-92b-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 177th target gene is the hsa-miR-3679-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 178th target gene is the hsa-miR-4792 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 179th target gene is the hsa-miR-3656 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 180th target gene is the hsa-miR-92a-2-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the target gene 181 is the hsa-miR-4466 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 182nd target gene is the hsa-miR-4513 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 183rd target gene is the hsa-miR-6781-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 184th target gene is the hsa-miR-4649-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 185th target gene is the hsa-miR-6775-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 186th target gene is the hsa-miR-4651 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 187th target gene is the hsa-miR-3195 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 188th target gene is the hsa-miR-6726-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 189th target gene is the hsa-miR-6872-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 190th target gene is the hsa-miR-371a-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 191st target gene is the hsa-miR-6777-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 192nd target gene is the hsa-miR-6789-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 193rd target gene is the hsa-miR-7975 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 194th target gene is the hsa-miR-6821-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 195th target gene is the hsa-miR-4534 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 196th target gene is an hsa-miR-619-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 197th target gene is the hsa-miR-7107-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 198th target gene is the hsa-miR-1228-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 199th target gene is the hsa-miR-6774-5p gene, their homologues, their transcripts, or their mutants or derivatives.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 200th target gene is the hsa-miR-6805-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 201st target gene is an hsa-miR-23a-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in expression of a gene or a transcription product thereof can be a marker for pancreatic cancer (Patent Document 3).
- the 202nd target gene is the hsa-miR-4665-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 203rd target gene is an hsa-miR-4505 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 204th target gene is the hsa-miR-4638-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 205th target gene is an hsa-miR-24-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 206th target gene is the hsa-miR-3135b gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 207th target gene is the hsa-miR-4745-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 208th target gene is the hsa-miR-128-1-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 209th target gene is the hsa-miR-4476 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 210th target gene is the hsa-miR-4687-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 211st target gene is the hsa-miR-3665 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 212th target gene is the hsa-miR-6806-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 213rd target gene is the hsa-miR-3937 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 214th target gene is the hsa-miR-711 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 215th target gene is the hsa-miR-3141 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 216th target gene is the hsa-miR-3188 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 217th target gene is the hsa-miR-4281 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 218th target gene is the hsa-miR-5196-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 219th target gene is the hsa-miR-6880-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 220th target gene is the hsa-miR-3960 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the target gene 221 is the hsa-miR-3648 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 1 above.
- the 222nd target gene is the hsa-miR-6721-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 223rd target gene is the hsa-miR-4492 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 224th target gene is the hsa-miR-744-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 225th target gene is the hsa-miR-7704 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 226th target gene is the hsa-miR-4749-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 227th target gene is the hsa-miR-6794-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof. So far, there is no report that changes in the expression of genes or their transcripts can serve as markers for pancreatic cancer.
- the 228th target gene is the hsa-miR-6511a-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof. So far, there is no report that changes in the expression of genes or their transcripts can serve as markers for pancreatic cancer.
- the 229th target gene is the hsa-miR-6824-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof. So far, there is no report that changes in the expression of genes or their transcripts can serve as markers for pancreatic cancer.
- the 230th target gene is an hsa-miR-762 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the target gene 231 is the hsa-miR-6836-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 232th target gene is the hsa-miR-6727-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the target gene 233 is the hsa-miR-4739 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 234th target gene is the hsa-miR-7777 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 235th target gene is the hsa-miR-4484 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 236th target gene is the hsa-miR-6515-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 237th target gene is the hsa-miR-373-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 238th target gene is the hsa-miR-4258 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 239th target gene is the hsa-miR-4675 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 240th target gene is the hsa-miR-3180 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the target gene 241 is the hsa-miR-6076 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 242nd target gene is the hsa-miR-1238-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the target gene 243 is the hsa-miR-4463 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 244th target gene is the hsa-miR-4486 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 245th target gene is the hsa-miR-4730 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 246th target gene is the hsa-miR-6766-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof. So far, there is no report that changes in the expression of genes or their transcripts can serve as markers for pancreatic cancer.
- the 247th target gene is the hsa-miR-4286 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer Patent Document 2 above.
- the 248th target gene is the hsa-miR-6511a-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof. So far, there is no report that changes in the expression of genes or their transcripts can serve as markers for pancreatic cancer.
- the 249th target gene is the hsa-miR-4739 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a report that changes in the expression of a gene or a transcription product thereof can serve as a marker for pancreatic cancer (Non-Patent Document 5).
- the 250th target gene is the hsa-miR-6749-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof. So far, there is no report that changes in the expression of genes or their transcripts can serve as markers for pancreatic cancer.
- nucleic acid probe or primer for detection of early pancreatic cancer or pancreatic cancer precursor lesion a nucleic acid capable of specifically binding to a target nucleic acid as the above-mentioned early pancreatic cancer or pancreatic cancer precursor lesion marker, It can be used as a nucleic acid for detecting or diagnosing early pancreatic cancer or pancreatic cancer precursor lesion, such as a nucleic acid probe or primer.
- the nucleic acid probe or primer that can be used for detecting early pancreatic cancer or pancreatic cancer precursor lesions, or for diagnosing early pancreatic cancer or pancreatic cancer precursor lesions, Human-derived hsa-miR-6784-5p, hsa-miR-1181, hsa-miR-671-5p, hsa-miR-6857-5p, hsa-miR-4276 as target nucleic acids for pancreatic cancer precursor lesions Hsa-miR-1914-3p, hsa-miR-149-3p, hsa-miR-937-5p, hsa-miR-4675, hsa-miR-6695-5p, hsa-miR-4731-5p, hsa-miR -5090, hsa-miR-3620-5p, hsa-miR-1343-5p, hsa-miR
- the above target nucleic acids may have increased or decreased expression levels depending on the type of the target nucleic acid in subjects suffering from early pancreatic cancer or pancreatic cancer precursor lesions compared to healthy subjects.
- crease / decrease exemplifies a change in the expression level of the target miRNA corresponding to SEQ ID NOs: 1 to 226 in the blood (serum) of a pancreatic cancer precursor lesion patient (human) relative to a healthy subject.
- any target miRNA selected this time and described in the specification can be used for detection and determination of early pancreatic cancer or pancreatic cancer precursor lesions in a subject.
- the expression level of the target nucleic acid is measured for body fluid derived from a subject (for example, human) suspected of suffering from early pancreatic cancer or pancreatic cancer precursor lesion, and body fluid derived from a healthy body. Can be effectively used to detect early pancreatic cancer or pancreatic cancer precursor lesions with high accuracy.
- body fluid derived from a subject suspected of suffering from early pancreatic cancer or pancreatic cancer precursor lesion for example, human
- advanced pancreatic cancer patient for example, biliary tract cancer patient
- breast cancer patient prostate
- prostate The amount of target nucleic acid expressed in body fluids derived from cancer patients, colon cancer patients, stomach cancer patients, esophageal cancer patients, liver cancer patients, pancreatic benign disease patients, prostate benign disease patients, or combinations thereof, and Can be effectively used to identify early pancreatic cancer or pancreatic cancer precursor lesions specifically and with high accuracy from other cancers or benign diseases.
- Nucleic acid probes or primers that can be used in the present invention are at least one, at least two, at least three, at least four, or at least five of SEQ ID NOs: 1-83, 227-229, 246, 248, and 250.
- Nucleic acid probes or primers that can be used in the present invention are further represented by at least one, at least two, at least three, at least four, or at least five of SEQ ID NOs: 84-226, 230-245, 247, and 249.
- a nucleic acid probe capable of specifically binding to a polynucleotide comprising the nucleotide sequence or at least one, at least two, at least three, at least four of SEQ ID NOs: 84 to 226, 230 to 245, 247, and 249
- a primer for amplifying a polynucleotide comprising a base sequence represented by at least 5.
- the nucleic acid probe or primer includes a polynucleotide group including a base sequence represented by any one of SEQ ID NOs: 1 to 250, or a base sequence in which u is t in the base sequence, and a complementary sequence thereof
- target miRNAs used in the present invention include, for example, precursor miRNAs as shown in SEQ ID NOs: 251 to 518 in Table 1, and isoform miRNAs as shown in SEQ ID NOs: 519 to 812 ( isomiRNA).
- Isotype miRNA includes those having a base number as short as about 15, those as long as about 29, and those having mutations such as substitution. Therefore, in the present invention, the nucleic acid probe or primer for enabling measurement of the expression of the precursor miRNA and the target isoform miRNA is also included as the nucleic acid probe or primer.
- These polynucleotides can be used as nucleic acid probes and primers for detecting the above-mentioned early pancreatic cancer or pancreatic cancer precursor lesion marker, which is a target nucleic acid.
- nucleic acid probes or primers that can be used in the present invention are at least one selected from the group consisting of any of the following polynucleotides (a) to (e) (that is, one or more). ) Polynucleotide.
- A a polynucleotide comprising the base sequence represented by any one of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, or a base sequence in which u is t in the base sequence, or a variant thereof A derivative thereof, or a fragment thereof comprising 15 or more consecutive bases
- B a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250
- C Comprising a base sequence complementary to the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248 and 250, or the base sequence in which u is t in the base sequence
- D including a base sequence complementary to the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 24
- the nucleic acid probe or primer that can be used in the present invention is the following: It may contain at least one (ie, one or more) polynucleotide shown in any of (f) to (j).
- the fragment containing 15 or more consecutive bases refers to, for example, 15 to less than the total number of bases in the sequence, 17 to less than the total number of bases in the sequence, 19 To less than the total number of bases in the sequence, etc., but not limited thereto.
- Any of the above polynucleotides or fragments thereof used in the present invention may be DNA or RNA.
- the above-mentioned polynucleotide that can be used in the present invention can be prepared using a general technique such as a DNA recombination technique, a PCR method, a method using a DNA / RNA automatic synthesizer.
- DNA recombination techniques and PCR methods include, for example, Ausubel et al., Current Protocols in Molecular Biology, John Willy & Sons, US (1993); Sambrook et al., Molecular Cloning A Laboratory A Laboratory. The techniques described can be used.
- Hsa-miR-6784-5p hsa-miR-1181, hsa-miR-671-5p, hsa-miR-6857-5p, hsa-miR-4276, hsa derived from human represented by SEQ ID NOs: 1-250 -MiR-1914-3p, hsa-miR-149-3p, hsa-miR-937-5p, hsa-miR-4675, hsa-miR-6695-5p, hsa-miR-4731-5p, hsa-miR-5090 Hsa-miR-3620-5p, hsa-miR-1343-5p, hsa-miR-6717-5p, hsa-miR-6825-5p, hsa-miR-6679-5p, hsa-miR-6769a-5p, hsa -M
- Such a nucleic acid probe or primer can be chemically synthesized using an automatic DNA synthesizer.
- the phosphoramidite method is used for this synthesis, and single-stranded DNA of up to about 100 bases can be automatically synthesized by this method.
- Automatic DNA synthesizers are commercially available from, for example, Polygen, ABI, Applied BioSystems, and the like.
- the polynucleotide of the present invention can also be prepared by a cDNA cloning method.
- a cDNA cloning method for example, microRNA Cloning Kit Wako can be used as the cDNA cloning technique.
- the sequence of the nucleic acid probe and the primer for detecting the polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 250 does not exist in the living body as miRNA or a precursor thereof.
- the base sequences represented by SEQ ID NO: 14 and SEQ ID NO: 118 are generated from the precursor represented by SEQ ID NO: 264, and this precursor has a hairpin-like structure as shown in FIG.
- the base sequences represented by SEQ ID NO: 14 and SEQ ID NO: 118 have mismatched sequences. For this reason, a completely complementary base sequence to the base sequence represented by SEQ ID NO: 14 or 118 is not naturally generated in vivo. Therefore, the nucleic acid probe and primer for detecting the base sequence represented by any of SEQ ID NOs: 1 to 250 have an artificial base sequence that does not exist in the living body.
- Early pancreatic cancer or pancreatic cancer precursor lesion detection kit or device The present invention is also used as a nucleic acid probe or primer in the present invention for measuring a target nucleic acid that is a marker of early pancreatic cancer or pancreatic cancer precursor lesion
- a kit or device for detecting early pancreatic cancer or pancreatic cancer precursor lesions comprising one or more possible polynucleotides (which may include variants, fragments, or derivatives) is provided.
- the target nucleic acid which is an early pancreatic cancer or pancreatic cancer precursor lesion marker in the present invention is at least one nucleic acid selected from the following group A.
- Group A hsa-miR-6784-5p, hsa-miR-1181, hsa-miR-671-5p, hsa-miR-6857-5p, hsa-miR-4276, hsa-miR-1914-3p, hsa-miR-149- 3p, hsa-miR-937-5p, hsa-miR-4675, hsa-miR-6695-5p, hsa-miR-4731-5p, hsa-miR-5090, hsa-miR-3620-5p, hsa-miR- 1343-5p, hsa-miR-6717-5p, hsa-miR-6825-5p, hsa-miR-6638-5p, hsa-miR-6769a-5p, hsa-miR-4728-5p,
- the additional target nucleic acid that can be used for the measurement is at least one nucleic acid selected from group B below.
- Group B hsa-miR-1908-5p, hsa-miR-6729-5p, hsa-miR-5195-3p, hsa-miR-638, hsa-miR-6125, hsa-miR-3178, hsa-miR-3196, hsa- miR-8069, hsa-miR-4723-5p, hsa-miR-4746-3p, hsa-miR-4689, hsa-miR-6816-5p, hsa-miR-6757-5p, hsa-miR-7109-5p, hsa-miR-6724-5p, hsa-miR-1225-3p, hsa-miR-6875-5p, hsa-miR-7108-5p, hsa-miR-4508, hsa-miR-6085, hs
- the kit or device of the present invention is a nucleic acid that can specifically bind to a target nucleic acid that is the aforementioned early pancreatic cancer or pancreatic cancer precursor lesion marker, preferably at least selected from the polynucleotides described in 2 above Includes one (or one or more) polynucleotides or variants thereof.
- the kit or device of the present invention includes a base sequence represented by any one of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, or a base in which u is t in the base sequence.
- the kit or device of the present invention further includes a base sequence represented by any of SEQ ID NOs: 84 to 226, 230 to 245, 247, and 249, or a base sequence in which u is t in the base sequence (or ),
- a polynucleotide comprising (or consisting of) a complementary sequence thereof, a polynucleotide that hybridizes with these polynucleotides under stringent conditions, or 15 or more, 17 or more of those polynucleotide sequences Or one or more, two or more, three or more, four or more, or five or more variants or fragments comprising 19 or more consecutive bases.
- the fragments that can be included in the kit or device of the present invention are, for example, one or more, two or more, three or more, four or more, or five selected from the group consisting of the following (1) to (2):
- the above polynucleotide (1) 15 or more, 17 or more, or 19 in the nucleotide sequence represented by any one of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, or a complementary sequence thereof, where u is t A polynucleotide comprising the above consecutive bases.
- nucleotide sequence represented by any of SEQ ID NOs: 84 to 226, 230 to 245, 247, and 249 in the nucleotide sequence where u is t or a complementary sequence thereof, 15 or more, 17 or more, or 19 or more A polynucleotide comprising consecutive bases.
- the polynucleotide is a base sequence represented by any one of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, or a base sequence in which u is t in the base sequence.
- a polynucleotide comprising a complementary sequence thereof, a polynucleotide that hybridizes with these polynucleotides under stringent conditions, or a variant comprising 15 or more, 17 or more, or 19 or more consecutive bases thereof. .
- the polynucleotide comprises a nucleotide sequence represented by any one of SEQ ID NOs: 84 to 226, 230 to 245, 247, and 249, or a nucleotide sequence in which u is t in the nucleotide sequence.
- a polynucleotide comprising a complementary sequence thereof, a polynucleotide that hybridizes with these polynucleotides under stringent conditions, or a variant comprising 15 or more, 17 or more, or 19 or more consecutive bases thereof. .
- the fragment may be a polynucleotide comprising 15 or more, 17 or more, or 19 or more consecutive bases.
- the size of a polynucleotide fragment is, for example, 15 to less than the total number of bases in the sequence, 17 to less than the total number of bases in the sequence, and 19 to less than the total number of bases in the sequence.
- the number of bases in the range is, for example, 15 to less than the total number of bases in the sequence, 17 to less than the total number of bases in the sequence, and 19 to less than the total number of bases in the sequence. The number of bases in the range.
- the above-mentioned combination constituting the kit or device of the present invention specifically includes the above-mentioned polynucleotide relating to the combination of SEQ ID NOs: shown in Table 1 (SEQ ID NOs: 1 to 250 corresponding to the miRNA markers in Table 1). Although they can be mentioned, they are merely exemplary and various possible combinations of polynucleotides that allow specific binding to other miRNA markers in Table 1 (corresponding to SEQ ID NOs: 251 to 812). All are intended to be encompassed by the present invention.
- the above-mentioned combination constituting the kit or device for distinguishing early pancreatic cancer or pancreatic cancer precursor lesion from a healthy body consists of, for example, a base sequence represented by a sequence number shown in Table 1. It is sufficient to combine two or more of the above polynucleotides, three or more, four or more, or five or more, and usually a sufficient performance can be obtained even with a combination of two.
- Base sequences represented by SEQ ID NOs: 1 to 250 as specific two combinations of base sequences for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies or their complementary sequences
- a polynucleotide comprising the nucleotide sequence represented by SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, which are newly found out of two combinations composed of the above-mentioned polynucleotides consisting of A combination comprising at least one (one or more) is preferred.
- polynucleotides comprising a base sequence for distinguishing early pancreatic cancer or pancreatic cancer precursor lesion from a healthy body or a complementary sequence thereof
- a plurality of combinations of at least one polynucleotide selected from the group consisting of polynucleotides consisting of a base sequence or a complementary sequence thereof and other polynucleotides of SEQ ID NOs are preferred.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 3 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 18 or a complementary sequence thereof are exemplified below.
- SEQ ID NOs: 90 and 18 (markers: hsa-miR-3196 and hsa-miR-6769a-5p) (2) SEQ ID NOs: 87 and 18 (markers: hsa-miR-638 and hsa-miR-6769a- (3) Combination of SEQ ID NOs: 89 and 18 (markers: hsa-miR-3178 and hsa-miR-6769a-5p) (4) SEQ ID NOs: 18 and 137 (markers: hsa-miR-6769a-5p) combination of hsa-miR-4673) (5) combination of SEQ ID NOs: 84 and 18 (markers: hsa-miR-1908-5p and hsa-miR-6769a-5p)
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the base sequence represented by SEQ ID NO: 12 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 20 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 1 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 15 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the base sequence represented by SEQ ID NO: 50 or a complementary sequence thereof are exemplified below.
- two polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- examples include the following including a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 63 or a complementary sequence thereof.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- a combination including a polynucleotide comprising the base sequence represented by SEQ ID NO: 72 or a complementary sequence thereof is exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 5 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 24 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 10 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 52 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 9 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the base sequence represented by SEQ ID NO: 11 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 19 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the base sequence represented by SEQ ID NO: 39 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide consisting of the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesion from a healthy body
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 61 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the base sequence represented by SEQ ID NO: 7 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 17 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 22 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide comprising the base sequence represented by SEQ ID NO: 26 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 74 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide comprising the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions from healthy bodies
- combinations including a polynucleotide consisting of the base sequence represented by SEQ ID NO: 21 or a complementary sequence thereof are exemplified below.
- polynucleotides comprising the above-mentioned polynucleotide consisting of the base sequence represented by SEQ ID NOs: 1 to 250 for distinguishing early pancreatic cancer or pancreatic cancer precursor lesion from a healthy body
- combinations including a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 28 or a complementary sequence thereof are exemplified below.
- polynucleotides having cancer type specificity that can distinguish early pancreatic cancer or pancreatic cancer precursor lesions from not only healthy bodies but also other cancers
- a plurality of combinations of at least one polynucleotide selected from (2) and a polynucleotide having other sequence number are preferred.
- polynucleotides having cancer types specific to distinguish early pancreatic cancer or pancreatic cancer precursor lesions from not only healthy subjects but also other cancers selected from cancer type specific polynucleotide group 1 A combination of a plurality of polynucleotides is more preferred.
- cancer type specific polynucleotide group 1 As a combination of polynucleotides having cancer types specific to distinguish early pancreatic cancer or pancreatic cancer precursor lesions from not only healthy subjects but also other cancers, selected from cancer type specific polynucleotide group 1 Among the combinations of the plurality of polynucleotides, for example, SEQ ID NOS: 119, 12, 28, 105, 137, 121, 109, 87, 5, 140, 106, 2 175, 90, 237 and 247 selected from the group consisting of polynucleotides consisting of the nucleotide sequences represented by them or their complementary sequences (hereinafter, this group is referred to as “cancer type-specific polynucleotide group 2”) More preferred is a combination of polynucleotides comprising at least one polynucleotide.
- the number of combinations of the above-mentioned cancer type-specific polynucleotides is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more. It is possible to combine these numbers, but more preferable is a combination of 5 or more. Usually, sufficient performance (accuracy, sensitivity, specificity, etc.) can be obtained with 5 combinations.
- a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 12 or a complementary sequence thereof and the sequence number of five polynucleotides selected from the cancer type-specific polynucleotide group 1 are represented. And a combination with a polynucleotide comprising a base sequence or a complementary sequence thereof.
- SEQ ID NOS: 12, 137, 119, 105, and 237 (markers: hsa-miR-5090, hsa-miR-4673, hsa-miR-6683-5p, hsa-miR-642a-3p, and hsa-miR-373 -2p) combinations
- SEQ ID NOs: 87, 12, 137, 119 and 105 (markers: hsa-miR-638, hsa-miR-5090, hsa-miR-4673, hsa-miR-6613-5p and hsa-
- SEQ ID NOS: 12, 103, 137, 105, and 247 (markers: hsa-miR-5090, hsa-miR-6085, hsa-miR-4673, and hsa-miR-642a-3p)
- hsa-miR-4286 SEQ
- polynucleotide selected from the polynucleotide consisting of the base sequence represented by SEQ ID NO: 28 or its complementary sequence and the cancer type-specific polynucleotide group 1.
- SEQ ID NO: 28 the base sequence represented by SEQ ID NO: 28 or its complementary sequence
- cancer type-specific polynucleotide group 1 The combination with the polynucleotide which consists of a base sequence or its complementary sequence is illustrated.
- SEQ ID NOs: 137, 119, 105, 28, and 237 (markers: hsa-miR-4673, hsa-miR-6683-5p, hsa-miR-642a-3p, hsa-miR-6782-5p, and hsa-miR -373-5p) combination
- SEQ ID NOs: 87, 106, 119, 28 and 121 markers: hsa-miR-638, hsa-miR-4695-5p, hsa-miR-6683-5p and hsa-miR- (6)
- SEQ ID NOs: 106, 137, 119, 28, and 121 (markers: hsa-miR-4695-5p, hsa-miR-4673, and hsa-miR-6813-5p)
- polynucleotide selected from the polynucleotide consisting of the base sequence represented by SEQ ID NO: 5 or its complementary sequence and the cancer type-specific polynucleotide group 1.
- SEQ ID NO: 5 the base sequence represented by SEQ ID NO: 5 or its complementary sequence
- cancer type-specific polynucleotide group 1 The combination with the polynucleotide which consists of a base sequence or its complementary sequence is illustrated.
- SEQ ID NOs: 90, 5, 137, 119 and 105 (markers: hsa-miR-3196, hsa-miR-4276, hsa-miR-4673, hsa-miR-6683-5p and hsa-miR-642a-3p)
- SEQ ID NOs: 5, 137, 119, 105 and 237 (markers: hsa-miR-4276, hsa-miR-4673, hsa-miR-6683-5p, hsa-miR-642a-3p and hsa- (3) SEQ ID NOs: 5, 137, 119, 105, and 32 (markers: hsa-miR-4276, hsa-miR-4673, hsa-miR-6683-5p, and hsa-miR-642a -3p and hsa-miR-6087)
- polynucleotide selected from the polynucleotide consisting of the base sequence represented by SEQ ID NO: 2 or its complementary sequence and the cancer type specific polynucleotide group 1
- SEQ ID NO: 2 the base sequence represented by SEQ ID NO: 2 or its complementary sequence
- cancer type specific polynucleotide group 1 The combination with the polynucleotide which consists of a base sequence or its complementary sequence is illustrated.
- SEQ ID NOs: 2, 137, 119, 105, and 237 (markers: hsa-miR-1181, hsa-miR-4673, hsa-miR-6683-5p, hsa-miR-642a-3p, and hsa-miR-373 -2p) combinations
- SEQ ID NOs: 2, 87, 137, 119 and 105 (markers: hsa-miR-1181, hsa-miR-638, hsa-miR-4673, hsa-miR-6683-5p and hsa-
- SEQ ID NOS: 2, 137, 119, 105, and 13 (markers: hsa-miR-1181, hsa-miR-4673, hsa-miR-6683-5p, and hsa-miR-642a -3p and hsa-miR-3620-5p)
- SEQ ID NOs of 5 polynucleotides selected from the polynucleotides consisting of the nucleotide sequences represented by SEQ ID NOS: 12 and 28 or their complementary sequences and the cancer type-specific polynucleotide group 1.
- SEQ ID NOs: 12, 137, 105, 28, and 247 (markers: hsa-miR-5090, hsa-miR-4673, hsa-miR-642a-3p, hsa-miR-6682-5p, and hsa-miR-4286 (2) SEQ ID NOS: 12, 137, 119, 105, and 28 (markers: hsa-miR-5090, hsa-miR-4673, hsa-miR-6683-5p, hsa-miR-642a-3p, and hsa- (3) SEQ ID NOs: 12, 103, 137, 105 and 28 (markers: hsa-miR-5090, hsa-miR-6085, hsa-miR-4673 and hsa-miR-642a-3p And hsa-miR-6782-5p) (4) SEQ ID NO:
- SEQ ID NOs of 5 polynucleotides selected from the polynucleotide consisting of the nucleotide sequences represented by SEQ ID NOS: 12 and 5 or their complementary sequences and the cancer-species specific polynucleotide group 1.
- SEQ ID NOs: 5, 12, 137, 119, and 105 (markers: hsa-miR-4276, hsa-miR-5090, hsa-miR-4673, hsa-miR-6683-5p, and hsa-miR-642a-3p)
- SEQ ID NOs: 90, 5, 12, 119 and 105 (markers: hsa-miR-3196, hsa-miR-4276, hsa-miR-5090, hsa-miR-6814-5p and hsa-miR-
- SEQ ID NOs: 5, 12, 137, 105, and 121 (markers: hsa-miR-4276, hsa-miR-5090, hsa-miR-4673, hsa-miR-642a-3p, and hsa -MiR-602) combination
- SEQ ID NOs of 5 polynucleotides selected from the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOS: 12 and 2 or a complementary sequence thereof and the cancer type-specific polynucleotide group 1.
- a combination with a polynucleotide comprising a nucleotide sequence or a complementary sequence thereof is represented by SEQ ID NOs of 5 polynucleotides selected from the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOS: 12 and 2 or a complementary sequence thereof and the cancer type-specific polynucleotide group 1.
- SEQ ID NOs: 2, 12, 137, 119 and 105 (markers: hsa-miR-1181, hsa-miR-5090, hsa-miR-4673, hsa-miR-6683-5p and hsa-miR-642a-3p)
- SEQ ID NOs: 2, 12, 137, 105, and 153 (markers: hsa-miR-1181, hsa-miR-5090, hsa-miR-4673, hsa-miR-642a-3p, and hsa-miR-)
- SEQ ID NO: 2, 12, 137, 105 and 121 (markers: hsa-miR-1181, hsa-miR-5090, hsa-miR-4673, hsa-miR-642a-3p and hsa -MiR-602) combination
- SEQ ID NOs of 5 polynucleotides selected from the polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOS: 5 and 2 or a complementary sequence thereof and the cancer type-specific polynucleotide group 1.
- SEQ ID NOS: 5 and 2 or a complementary sequence thereof
- the cancer type-specific polynucleotide group 1 The combination with the polynucleotide which consists of a base sequence or its complementary sequence is illustrated.
- SEQ ID NOs: 2, 90, 5, 119 and 105 markers: hsa-miR-1181, hsa-miR-3196, hsa-miR-4276, hsa-miR-6683-5p and hsa-miR-642a-3p
- SEQ ID NOs: 2, 5, 119, 109, and 121 markers: hsa-miR-1181, hsa-miR-4276, hsa-miR-6683-5p, hsa-miR-6769b-5p, and hsa- (3) SEQ ID NOs: 2, 5, 119, 86 and 121 (markers: hsa-miR-1181, hsa-miR-4276, hsa-miR-6683-5p and hsa-miR-5195-3p And hsa-miR-602)
- a polynucleotide comprising the nucleotide sequence represented by SEQ ID NOs: 12, 28, and 5 or a complementary sequence thereof and five polynucleotides selected from the cancer-species polynucleotide group 1
- the combination with the polynucleotide which consists of a base sequence represented by sequence number or its complementary sequence is illustrated.
- SEQ ID NOs: 5, 12, 1, 28 and 121 markers: hsa-miR-4276, hsa-miR-5090, hsa-miR-6784-5p, hsa-miR-6878-5p and hsa-miR-602
- the kit or device of the present invention detects early pancreatic cancer or pancreatic cancer precursor lesions in addition to the above-described polynucleotide of the present invention (which may include a variant, fragment or derivative). Also known polynucleotides that enable or polynucleotides that may be found in the future can be included.
- the kit of the present invention includes CEA, CA19-9, Span-1, DUPAN-2, CA50, CA242, TAG-72, in addition to the polynucleotide of the present invention described above and a variant or fragment thereof.
- Antibodies for measuring known early pancreatic cancer or pancreatic cancer precursor lesion test markers such as urinary fucose, POA and TPS can also be included.
- polynucleotides included in the kit of the present invention, and variants or fragments thereof can be individually or arbitrarily combined and packaged in different containers.
- the kit of the present invention can include a kit for extracting nucleic acid (for example, total RNA) from body fluids, cells or tissues, a fluorescent substance for labeling, an enzyme and medium for nucleic acid amplification, instructions for use, and the like.
- nucleic acid for example, total RNA
- the device of the present invention is a device for measuring a cancer marker in which a nucleic acid such as a polynucleotide, a variant thereof, a derivative thereof, or a fragment thereof in the present invention described above is bound or attached to a solid phase, for example. is there.
- a nucleic acid such as a polynucleotide, a variant thereof, a derivative thereof, or a fragment thereof in the present invention described above is bound or attached to a solid phase, for example. is there.
- the material of the solid phase are plastic, paper, glass, silicon, and the like. From the viewpoint of ease of processing, a preferable material of the solid phase is plastic.
- the shape of the solid phase is arbitrary, for example, a square shape, a round shape, a strip shape, a film shape and the like.
- the device of the present invention includes, for example, a device for measurement by a hybridization technique, and specific examples include a blotting device, a nucleic acid array (for example, a microarray, a DNA chip, an RNA chip, etc.).
- a blotting device for example, a blotting device, a nucleic acid array (for example, a microarray, a DNA chip, an RNA chip, etc.).
- the nucleic acid array technology uses a high-density dispenser called a spotter or arrayer on the surface of a solid phase that has been subjected to surface treatment such as introduction of functional groups such as L-lysine coat, amino group, and carboxyl group as necessary.
- the method of spotting nucleic acids the method of spraying nucleic acids onto a solid phase using an inkjet that ejects fine droplets from a nozzle with a piezoelectric element, the method of sequentially synthesizing nucleotides on a solid phase, etc.
- an array such as a chip is prepared by binding or attaching each of the nucleic acids one by one, and the target nucleic acid is measured using hybridization using this array.
- the kit or device of the present invention comprises at least one, preferably at least 2, more preferably at least 3, and most preferably at least 5 miRNAs that are markers of early pancreatic cancer or pancreatic cancer precursor lesions of Group 1 above.
- the kit or device of the present invention may optionally further comprise at least one, preferably at least two, more preferably at least three, most preferably miRNA that is a marker of early pancreatic cancer or pancreatic cancer precursor lesion of group 2 above.
- it can contain a nucleic acid capable of specifically binding to at least 5 to all of the polynucleotides.
- the kit or device of the present invention can be used for the detection of the following early pancreatic cancer or pancreatic cancer precursor lesion.
- the subject becomes an early pancreatic cancer or pancreatic cancer precursor lesion
- Early pancreatic cancer or pancreatic cancer in a subject comprising assessing in vitro whether it is affected and thereby detecting the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions in the subject
- a method for detecting a precursor lesion is provided.
- the above method of the present invention enables early diagnosis of cancer with minimal invasiveness, high sensitivity and specificity, thereby leading to early treatment and improvement of prognosis, as well as monitoring disease aversion and surgical Enables monitoring of the effectiveness of radiotherapeutic and chemotherapeutic treatments.
- 3D-Gene registered trademark
- RNA extraction reagent liquid sample kit Toray Industries, Inc. It is particularly preferable to adjust by adding a reagent for RNA extraction in (1), but a general acidic phenol method (Acid Guanidinium-Phenol-Chloroform (AGPC) method) may be used, or Trizol (registered trademark) (Life) (Technologies) may be used, or may be prepared by adding an RNA extraction reagent containing acidic phenol such as Trizol (life technologies) or Isogen (Nippon Gene, Japan). Furthermore, kits such as miRNeasy (registered trademark) Mini Kit (Qiagen) can be used, but are not limited to these methods.
- AGPC Acid Guanidinium-Phenol-Chloroform
- Trizol registered trademark
- Isogen Nippon Gene, Japan
- kits such as miRNeasy (registered trademark) Mini Kit (Qiagen) can be used, but are not limited to these methods.
- the present invention also provides use of the kit or device of the present invention for in vitro detection of an expression product of miRNA gene derived from early pancreatic cancer or pancreatic cancer precursor lesion in a subject-derived specimen. .
- the kit or device is used as described above, and includes a single or any possible combination of polynucleotides that can be used in the present invention.
- the polynucleotide contained in the kit or device of the present invention can be used as a probe or a primer.
- a primer Life Technologies' TaqMan (registered trademark) MicroRNA Assays, Qiagen's miScript PCR System, and the like can be used, but are not limited thereto.
- the polynucleotide contained in the kit or device of the present invention is a nucleotide sequence of a polynucleotide obtained by a hybridization technique such as Northern blotting, Southern blotting, in situ hybridization, Northern hybridization, Southern hybridization, or a sequencer.
- a hybridization technique such as Northern blotting, Southern blotting, in situ hybridization, Northern hybridization, Southern hybridization, or a sequencer.
- a hybridization technique such as Northern blotting, Southern blotting, in situ hybridization, Northern hybridization, Southern hybridization, or a sequencer.
- a method for specifically detecting a specific gene such as a technique for identifying a gene and a quantitative amplification technique such as a quantitative RT-PCR method
- body fluid such as blood, serum, plasma, urine, etc. of the subject is collected according to the type of detection method used.
- total RNA prepared by the above-described method may be used, or various polynucleotides containing cDNA
- the kit or device of the present invention is useful for diagnosis of early pancreatic cancer or pancreatic cancer precursor lesion or detection of the presence or absence of disease.
- the detection of early pancreatic cancer or pancreatic cancer precursor lesion using the kit or device is performed using blood, serum, plasma from a subject suspected of suffering from early pancreatic cancer or pancreatic cancer precursor lesion. It can be performed by detecting in vitro the expression level of a gene detected with a nucleic acid probe or primer contained in the kit or device using a sample such as urine.
- a sample such as urine.
- At least one of SEQ ID NOs: 1-83, 227-229, 246, 248, and 250 in specimens such as blood, serum, plasma, urine, etc.
- the expression level of the target miRNA marker measured by a polynucleotide consisting of (including variants, fragments or derivatives thereof) is the expression level in a sample such as blood, serum, plasma or urine of a healthy body If there is a statistically significant difference compared to, the subject can be evaluated as having early pancreatic cancer or pancreatic cancer precursor lesions.
- the method of the present invention can be combined with diagnostic imaging methods such as abdominal ultrasonography, CT scan, endoscopic retrograde pancreatography, and ultrasonic endoscopy.
- diagnostic imaging methods such as abdominal ultrasonography, CT scan, endoscopic retrograde pancreatography, and ultrasonic endoscopy.
- the method of the present invention can specifically detect early pancreatic cancer or pancreatic cancer precursor lesions, and can be substantially distinguished from cancers other than early pancreatic cancer or pancreatic cancer precursor lesions. it can.
- these cancers can be identified by combining with other diagnostic methods such as the image diagnostic methods described above.
- a method for detecting that an early pancreatic cancer or pancreatic cancer precursor lesion is not included in a subject-derived specimen using the kit or device of the present invention, or that an early pancreatic cancer or pancreatic cancer precursor lesion is included Is a method of collecting a body fluid such as blood, serum, plasma, urine, etc. of a subject and expressing the expression level of a target gene (or target nucleic acid) contained therein in one or more selected from the polynucleotide group of the present invention.
- the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesion is evaluated by measuring using the polynucleotide (including mutant, fragment or derivative) of Including detecting.
- the method for detecting early pancreatic cancer or pancreatic cancer precursor lesion of the present invention is a known or developing pancreas for the purpose of treating or improving the disease in patients with early pancreatic cancer or pancreatic cancer precursor lesion, for example.
- Cancer-related therapeutics include TS-1 (a combination of tegafur, gimeracil, and oteracil potassium), gemzar (gemcitabine hydrochloride), tarceva (erlotinib hydrochloride), 5-FU (fluorouracil) , Levofolinate, irinotecan, oxaliplatin, abraxane (nabupaclitaxel), combinations thereof, etc.
- TS-1 a combination of tegafur, gimeracil, and oteracil potassium
- gemzar gemcitabine hydrochloride
- tarceva tarceva
- 5-FU fluorouracil
- Levofolinate irinotecan
- oxaliplatin oxa
- the method of the present invention includes, for example, the following steps (a), (b) and (c): (A) contacting a specimen from a subject with a polynucleotide in a kit or device of the present invention in vitro; (B) measuring the expression level of the target nucleic acid in the specimen using the polynucleotide as a nucleic acid probe or primer; (C) Based on the result of (b), it is evaluated whether or not the subject suffers from early pancreatic cancer or pancreatic cancer precursor lesion (cell), thereby causing early pancreatic cancer or pancreatic in the subject. Detecting the presence or absence of cancer precursor lesions (cells); Can be included.
- blood, serum or plasma can be used as a preferred sample.
- the expression level is measured using a technique such as a hybridization technique such as a nucleic acid array method, a technique for specifying a nucleotide sequence of a polynucleotide using a sequencer, a quantitative amplification technique such as a quantitative RT-PCR method, etc. Can be done by.
- a technique such as a hybridization technique such as a nucleic acid array method, a technique for specifying a nucleotide sequence of a polynucleotide using a sequencer, a quantitative amplification technique such as a quantitative RT-PCR method, etc.
- the expression level of the target nucleic acid in the specimen of the subject is changed to the expression level of the target nucleic acid in the specimen derived from the healthy subject or the benign pancreatic disease ("Reference” or "Control”). If there is a statistically significant difference in comparison with the control)), the subject is identified as early pancreatic by the discrimination score created from the expression level of the target nucleic acid in the sample of the subject and the discriminant (described later). It can be evaluated as having cancer or pancreatic cancer precursor lesion.
- the present invention relates to miR-6784-5p, miR-1181, miR-671-5p, miR-6857-5p, miR-4276, miR-1914-3p, miR-149-3p, miR-937. -5p, miR-4675, miR-6695-5p, miR-4731-5p, miR-5090, miR-3620-5p, miR-1343-5p, miR-6717-5p, miR-6825-5p, miR-6638 -5p, miR-6769a-5p, miR-4728-5p, miR-652-5p, miR-4257, miR-6785-5p, miR-7110-5p, miR-6687-5p, miR-887-3p, miR -1228-5p, miR-5572, miR-6782-5p, miR-429 MiR-6786-5p, miR-5010-5p, miR-6087, miR-6765-5p, miR-6732-5p, miR
- evaluation may be a judgment by a doctor, or is an evaluation support based on a result of an in vitro examination that is not a judgment by a doctor.
- miR-6784-5p is hsa-miR-6784-5p
- miR-1181 is hsa-miR-1181
- miR-671-5p is hsa.
- miR-671-5p is hsa.
- miR-6857-5p is hsa-miR-6857-5p
- miR-4276 is hsa-miR-4276
- miR-1914-3p is hsa-miR-1914-3p
- MiR-149-3p is hsa-miR-149-3p
- miR-937-5p is hsa-miR-937-5p
- miR-4675 is hsa-miR-4675
- miR-6695 -5p is hsa-miR-6695-5p and miR-4731-5p is hsa-miR-47 1-5p
- miR-5090 is hsa-miR-5090
- miR-6675-5p is hsa-miR-6675-5p
- miR-6798-5p is hsa-miR-6798-5p
- miR-6131 is hsa-miR-6131
- miR-4667-5p is hsa-miR-4667-5p
- miR-6510-5p is hsa-miR-6510-5p
- miR-4690-5p is hsa-miR-4690-5p
- miR- 920 is hsa-miR-920
- miR-23b-3p is hsa-miR-23b-3p
- miR-4448 is hsa-miR-4448
- miR-2110 is hsa-miR-2110
- miR-4706 is hsa-miR-4706
- miR-7845-5p is hsa-m R-7845-5p
- the nucleic acid is a polynucleotide shown in any of the following (a) to (e): (A) a polynucleotide comprising the base sequence represented by any one of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, or a base sequence in which u is t in the base sequence, or a variant thereof A derivative thereof, or a fragment thereof comprising 15 or more consecutive bases, (B) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250, (C) Comprising a base sequence complementary to the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248 and 250, or the base sequence in which u is t in the base sequence A polynucleotide, a variant thereof, a derivative
- nucleic acids in the methods of the present invention further include miR-1908-5p, miR-6729-5p, miR-5195-3p, miR-638, miR-6125, miR-3178, miR-3196, miR-8069, miR- 4723-5p, miR-4746-3p, miR-4589, miR-6816-5p, miR-6757-5p, miR-7109-5p, miR-6724-5p, miR-1225-3p, miR-6875-5p, miR-7108-5p, miR-4508, miR-6085, miR-6679-5p, miR-642a-3p, miR-4695-5p, miR-7847-3p, miR-3197, miR-6769b-5p, miR- 7641, miR-187-5p, miR-3185, iR-2861, miR-3940-5p, miR-1203, miR-615-5p, miR-4787-5p, miR-1343-3p, miR-6
- miR-1908-5p is hsa-miR-1908-5p
- miR-6729-5p is hsa-miR-6729-5p
- miR-5195-3p is hsa-miR-5195-3p.
- MiR-638 is hsa-miR-638, miR-6125 is hsa-miR-6125, miR-3178 is hsa-miR-3178, miR-3196 is hsa-miR-3196 , MiR-8069 is hsa-miR-8069, miR-4723-5p is hsa-miR-4723-5p, miR-4746-3p is hsa-miR-4746-3p, and miR-4629 is hsa -MiR-4689, miR-6816-5p is hsa-miR-681 -5p, miR-6757-5p is hsa-miR-6757-5p, miR-7109-5p is hsa-miR-7109-5p, miR-6724-5p is hsa-miR-6724-5p MiR-1225-3p is hsa-miR-1225-3p, miR-6875-5p is
- the polynucleotide in which the nucleic acid is represented by any of the following (f) to (j):
- G a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 84 to 226, 230 to 245, 247, and 249
- specimens prepared from a biological tissue (preferably pancreatic tissue) of a subject include specimens prepared from a biological tissue (preferably pancreatic tissue) of a subject, body fluid such as blood, serum, plasma, urine and the like.
- body fluid such as blood, serum, plasma, urine and the like.
- a biological tissue extracted by surgery, etc. from which a specimen for measurement can be prepared.
- subject refers to, for example, mammals, but not limited to primates such as humans and monkeys, rodents such as mice and rats, pets such as dogs and cats, and horses. It refers to animals, animals kept in zoos, etc., preferably humans.
- the steps can be changed according to the type of specimen used as a measurement target.
- RNA When RNA is used as a measurement object, detection of early pancreatic cancer or pancreatic cancer precursor lesion (cell) in a subject is, for example, the following steps (a), (b) and (c): (A) binding RNA prepared from a specimen of a subject or a complementary polynucleotide (cDNA) transcribed therefrom to a polynucleotide in the kit or device of the present invention; (B) RNA derived from a specimen bound to the polynucleotide or cDNA synthesized from the RNA by hybridization using the polynucleotide as a nucleic acid probe, by a sequencer that specifies the base sequence of the polynucleotide, or Quantitatively or qualitatively measuring by quantitative RT-PCR using the polynucleotide as a primer, (C) Based on the measurement result of (b) above, the subject is suffering from early pancreatic cancer or pancreatic cancer precursor lesion compared to the control, or early pancre
- hybridization methods can be used for detecting, examining, evaluating or diagnosing early pancreatic cancer or pancreatic cancer precursor lesion (derived gene expression) in vitro according to the present invention.
- Such hybridization methods include, for example, Northern blotting, Southern blotting, RT-PCR, DNA chip analysis, in situ hybridization, Northern hybridization, Southern hybridization, sequencer, etc.
- a technique for identifying a base sequence can be used.
- the presence or absence of each gene expression in RNA and the expression level thereof can be detected and measured by using the nucleic acid probe that can be used in the present invention.
- radioisotope nucleic acid probe complementary strand
- a signal derived from the formed DNA / RNA double-stranded label is detected with a radiation detector (BAS-1800II (Fuji Photo Film Co., Ltd.). , Japan), or the like) or a fluorescence detector (STORM 865 (GE Healthcare), etc.) can be used for detection and measurement.
- RNA and the expression level thereof can be detected or measured by using the above-described primers that can be used in the present invention.
- cDNA was prepared from RNA derived from the biological tissue of the subject according to a conventional method, and prepared from the detection composition of the present invention so that each target gene region could be amplified using this as a template.
- a method of detecting a double-stranded DNA obtained by hybridizing a pair of primers (consisting of a positive strand and a reverse strand that binds to the cDNA) with cDNA and performing PCR by a conventional method can be exemplified. .
- a method for detecting double-stranded DNA a method in which the PCR is carried out using a primer previously labeled with a radioisotope or a fluorescent substance, a PCR product is electrophoresed on an agarose gel, and is then detected with ethidium bromide or the like.
- a method of detecting by staining the double-stranded DNA and a method of detecting the double-stranded DNA produced by transferring it to a nylon membrane or the like according to a conventional method and hybridizing with a labeled nucleic acid probe can be included.
- RNA and its expression level can be detected or measured from the number of reads by using the above-described primers that can be used in the present invention.
- cDNA was prepared from RNA derived from the biological tissue of the subject according to a conventional method, and prepared from the detection composition of the present invention so that each target gene region could be amplified using this as a template.
- a pair of primers consisting of a normal strand and a reverse strand that binds to the above cDNA are hybridized with cDNA and subjected to PCR by a conventional method.
- a method of detecting and measuring with a sequencer such as System (Thermo Fisher Scientific Co., Ltd.) can be exemplified.
- a method of detecting and measuring RNA derived from biological tissue of a subject with PacBio RS II (Pacific Biosciences) without amplifying by PCR method can be exemplified.
- RNA chip or DNA chip in which the above-described detection composition of the present invention is attached to a substrate (solid phase) as a nucleic acid probe (single strand or double strand) is used. .
- the region where the nucleic acid probe is attached is called a probe spot, and the region where the nucleic acid probe is not attached is called a blank spot.
- a gene group immobilized on a substrate generally has a name such as a nucleic acid chip, a nucleic acid array, or a microarray.
- a DNA or RNA array includes a DNA or RNA macroarray and a DNA or RNA microarray.
- the term “chip” includes the array.
- 3D-Gene (registered trademark) Human miRNA Oligo chip can be used, but is not limited thereto.
- the measurement of the DNA chip is not limited.
- a signal derived from the label of the detection composition is detected using an image detector (Typhoon 9410 (GE Healthcare), 3D-Gene (registered trademark) scanner (Toray Industries, Inc.), etc.
- image detector Typhoon 9410 (GE Healthcare), 3D-Gene (registered trademark) scanner (Toray Industries, Inc.), etc.
- the method of detecting and measuring can be illustrated.
- stringent conditions means that the nucleic acid probe is detectable to a greater extent than the other sequences as described above (eg, average of background measurements + standard of background measurements). (Measurement value of error x 2 or more)).
- Stringent conditions are defined by hybridization and subsequent washing.
- the hybridization conditions are not limited, but for example, 30 to 60 ° C. and 1 to 24 hours in a solution containing SSC, surfactant, formamide, dextran sulfate, blocking agent and the like.
- 1 ⁇ SSC is an aqueous solution (pH 7.0) containing 150 mM sodium chloride and 15 mM sodium citrate, and the surfactant includes SDS (sodium dodecyl sulfate), Triton, or Tween.
- More preferable hybridization conditions include 3 to 10 ⁇ SSC and 0.1 to 1% SDS.
- the washing conditions after hybridization which is another condition for defining stringent conditions, include, for example, a solution containing 0.5 ⁇ SSC and 0.1% SDS at 30 ° C., and 0 at 30 ° C. Conditions such as continuous washing with a solution containing 2 ⁇ SSC and 0.1% SDS and a 0.05 ⁇ SSC solution at 30 ° C. can be mentioned. It is desirable that the complementary strand maintain a hybridized state with the target positive strand even when washed under such conditions. Specifically, as such a complementary strand, a strand consisting of a base sequence that is completely complementary to the target positive strand base sequence, and at least 80%, preferably at least 85%, more preferably, the strand. Examples include strands consisting of a base sequence having at least 90% or at least 95% identity, such as at least 98% or at least 99%.
- a PCR buffer having a composition such as 10 mM Tris-HCL (pH 8.3), 50 mM KCL, 1 to 2 mM MgCl 2 is used.
- the treatment may be performed for 15 seconds to 1 minute at a Tm value calculated from the primer sequence +5 to 10 ° C.
- Tm value 2 ⁇ (number of adenine residues + number of thymine residues) + 4 ⁇ (number of guanine residues + number of cytosine residues).
- Calculation of gene expression level is not limited, but for example, statistical analysis of gene expression microarray data (Speed T., Chapman and HalliCensalCensitiveChemistralus. Et al., Blackwell publishing) can be used in the present invention.
- a spot can be regarded as a detection spot.
- the average value of the measured value of the blank spot can be regarded as the background, and can be subtracted from the measured value of the probe spot to obtain the gene expression level.
- the missing value of the gene expression level is excluded from the analysis target, preferably replaced with the minimum value of the gene expression level in each DNA chip, or more preferably 0.1 from the logarithmic value of the minimum value of the gene expression level. Can be replaced with the subtracted value.
- the number of samples to be measured is 20% or more, preferably 50% or more, more preferably 80% or more, 2 6, preferably 2 8, more preferably 2 Only genes having a gene expression level of the 10th power or higher can be selected as an analysis target. Examples of normalization of gene expression levels include, but are not limited to, global normalization and quantile normalization (Bolstad, B. M. et al., 2003, Bioinformatics, Vol. 19, p185-193).
- the present invention also measures the expression level of a target gene in a specimen derived from a subject using the diagnostic polynucleotide, kit, device (for example, chip) of the present invention, or a combination thereof, and enables early pancreatic cancer or Early pancreatic cancer, which was created using the gene expression level of a specimen from a subject (or patient) known to have a pancreatic cancer precursor lesion and the gene expression level of a specimen from a healthy subject as a teacher sample, or By substituting the expression level of the target gene in the specimen derived from the subject into the discriminant (discriminant function) that can discriminate between pancreatic cancer precursor lesions and healthy, A method of detecting (or assisting in detection) early pancreatic cancer or pancreatic cancer precursor lesions in a subject, comprising assessing the presence or absence of cancer or pancreatic cancer precursor lesions.
- the present invention further includes using the diagnostic polynucleotide, kit, device (eg, chip), or combination thereof of the present invention, wherein the subject includes early pancreatic cancer or pancreatic cancer precursor lesions, and / or A first step of measuring in vitro the expression level of a target gene in a plurality of specimens known not to contain early pancreatic cancer or pancreatic cancer precursor lesion, the target gene obtained in the first step.
- the discriminant is any discriminant analysis method capable of creating a discriminant that distinguishes early pancreatic cancer or pancreatic cancer precursor lesion from healthy, for example, Fisher discriminant analysis, Mahalanobis distance Can be created using a nonlinear discriminant analysis, neural network, Support Vector Machine (SVM), etc., but is not limited to these specific examples.
- Fisher discriminant analysis Fisher discriminant analysis
- Mahalanobis distance Can be created using a nonlinear discriminant analysis, neural network, Support Vector Machine (SVM), etc., but is not limited to these specific examples.
- Linear discriminant analysis is a method for discriminating group membership using Equation 1 as a discriminant when the boundary of grouping is a straight line or a hyperplane.
- x is an explanatory variable
- w is a coefficient of the explanatory variable
- w 0 is a constant term.
- the value obtained by the discriminant is called the discriminant score
- the measured value of the newly given data set is substituted into the discriminant as an explanatory variable
- the grouping is discriminated by the sign (+ or-) of the discriminant score Can do.
- Fisher's discriminant analysis which is a type of linear discriminant analysis, is a dimension reduction method for selecting a dimension suitable for class discrimination. Focusing on the variance of composite variables, the data with the same label is used. Combining highly discriminating synthetic variables by minimizing the variance (Venables, W. N. et al., Modern Applied Statistics with S. Fourth edition. Springer., 2002).
- a projection direction w that maximizes Equation 2 is obtained.
- ⁇ is the average of inputs
- ng is the number of data belonging to class g
- ⁇ g is the average of inputs of data belonging to class g.
- the numerator and denominator have inter-class variance and intra-class variance when the data is projected in the direction of the vector w, and the discriminant coefficient w i is obtained by maximizing this ratio.
- the Mahalanobis distance is calculated by Equation 3 in consideration of data correlation, and can be used as a nonlinear discriminant analysis for discriminating a group having a close Mahalanobis distance from each group as a belonging group.
- ⁇ is the center vector of each group
- S ⁇ 1 is the inverse matrix of the variance-covariance matrix of that group.
- the center vector is calculated from the explanatory variable x, and an average vector or a median vector can be used.
- a boundary surface called a hyperplane is used to correctly classify the data set into a known grouping, with specific data items in the data set with a known grouping as explanatory variables and the grouping to be classified as an objective variable. And determine a discriminant for classifying data using the boundary surface.
- the discriminant can determine the grouping by substituting the measured value of the newly given data set into the discriminant as an explanatory variable. Further, the discrimination result at this time may be a group to be classified, may be a probability of being classified into a group to be classified, or may be a distance from a hyperplane.
- a method for dealing with a non-linear problem a method is known in which a feature vector is non-linearly transformed into a higher dimension and linear identification is performed in the space.
- An expression in which the inner product of two elements in a non-linearly mapped space is expressed only by the input in the original space is called a kernel.
- a kernel a linear kernel, RBF (Radial Basis Function) Kernel and Gaussian kernel.
- the optimal discriminant that is, the discriminant, can be constructed only by calculating the kernel while avoiding the calculation of the features in the mapped space while actually mapping in high dimensions by the kernel (for example, Hideki Aso et al.
- C-support vector classification (C-SVC), a kind of SVM method, creates a hyperplane by learning with two explanatory variables to determine which group an unknown data set falls into (C. Cortes et al., 1995, Machine Learning, 20, p273-297). *
- a data set (hereinafter referred to as “learning sample group”) composed of comprehensive gene expression levels of the two groups of serum-derived specimens is prepared, and there is a clear difference in gene expression levels between the two groups.
- the discriminant by C-SVC is determined with the gene as the explanatory variable and the grouping as the target variable (eg, -1 and +1).
- Equation 4 is an objective function to be optimized, where e is all input vectors, y is an objective variable, a is a Lagrange undetermined multiplier vector, Q is a positive definite matrix, and C is a parameter for adjusting the constraint condition.
- Equation 5 is the discriminant finally obtained, and the group to which it belongs can be determined by the sign of the value obtained by the discriminant.
- x is a support vector
- y is a label indicating group membership
- a is a corresponding coefficient
- b is a constant term
- K is a kernel function.
- Equation 6 an RBF kernel defined by Equation 6 can be used.
- x represents a support vector
- ⁇ represents a kernel parameter that adjusts the complexity of the hyperplane.
- Methods such as neural network, k-neighbor method, decision tree, logistic regression analysis can be selected.
- the method of the present invention comprises, for example, the following steps (a), (b) and (c): (A) in specimens already known to be from patients with early pancreatic cancer or pancreatic cancer precursor lesions and from healthy subjects or subjects without early pancreatic cancer or pancreatic cancer precursor lesions Measuring the expression level of the target gene using the detection polynucleotide, kit or device (eg, DNA chip) according to the present invention; (B) creating a discriminant of the above formulas 1 to 3, 5 and 6 from the measured value of the expression level measured in (a), (C) The expression level of the target gene in the subject-derived specimen is measured using the diagnostic (detection) polynucleotide, kit or device (for example, a DNA chip) according to the present invention, and the discrimination created in (b) Substitute them into the formula and determine or evaluate that the subject contains or does not include early pancreatic cancer or pancreatic cancer precursor lesions based on the results obtained, or early pancreatic cancer or pancreatic cancer
- x in the formulas 1 to 3, 5 and 6 is an explanatory variable, and includes a value obtained by measuring a polynucleotide selected from the polynucleotides described in Section 2 above or a fragment thereof.
- the explanatory variable for discriminating a patient from an early pancreatic cancer or pancreatic cancer precursor lesion of the present invention is, for example, a gene expression selected from any of the following (1) to (2): Amount.
- the expression between two groups consisting of the early pancreatic cancer or pancreatic cancer precursor lesion patient group and the healthy body group in the learning sample group is necessary. It is necessary to use a gene with a clear difference in quantity in the discriminant.
- the gene used as the explanatory variable of the discriminant is determined as follows.
- the P-value of t-test which is a parametric analysis, using the comprehensive gene expression level of a group of early-stage pancreatic cancer or pancreatic cancer precursor lesions as a learning sample group and the exhaustive gene expression level of a healthy body group as a data set
- the P value of the Mann-Whitney U test or the P value of the Wilcoxon test which is nonparametric analysis
- Bonferroni correction for example, by multiplying the P value obtained by the test by the number of test repetitions, that is, the number of genes used in the analysis, and comparing it with the desired significance level, the first type of error in the entire test is obtained. Probability of occurrence can be suppressed.
- the absolute value of the expression ratio of the median value of each gene expression level (Fold change) between the gene expression level of the early pancreatic cancer or pancreatic cancer precursor lesion patient group and the gene expression level of the healthy subject group, not the test. ) May be calculated and a gene used as an explanatory variable of the discriminant may be selected. Moreover, even if an ROC curve is created using the gene expression levels of the early pancreatic cancer or pancreatic cancer precursor lesion patient group and the healthy body group, and the gene used for the explanatory variable of the discriminant is selected based on the AUROC value Good.
- a discriminant that can be calculated by the above-described various methods is created using an arbitrary number of genes having a large difference in gene expression level obtained here.
- a method of constructing a discriminant that obtains the maximum discriminating accuracy for example, a method of constructing a discriminant with any combination of genes satisfying the significance level of the P value, or a gene used to create a discriminant, gene expression There is a method in which evaluation is repeated while increasing one by one in descending order of the amount of difference (Furey TS. Et al., 2000, Bioinformatics., Vol. 16, p906-14).
- this independent early pancreatic cancer or pancreatic cancer precursor lesion patient By substituting the gene expression level of another independent early pancreatic cancer or pancreatic cancer precursor lesion or healthy body into the explanatory variable for this discriminant, this independent early pancreatic cancer or pancreatic cancer precursor lesion patient Alternatively, the discrimination result of the group to which the healthy body belongs is calculated. That is, to detect a more universal early pancreatic cancer or pancreatic cancer precursor lesion by evaluating the discriminant constructed using the found diagnostic gene set and the diagnostic gene set in an independent sample group Can be found and a method for discriminating early pancreatic cancer or pancreatic cancer precursor lesions.
- the Split-sample method for evaluating the discriminating performance (generalization) of the discriminant In other words, the data set is divided into a learning sample group and a verification sample group, the gene selection and the discriminant creation by statistical test are performed in the learning sample group, and the verification sample group is discriminated by the discriminant formula and the verification sample group The accuracy, sensitivity, and specificity are calculated using the true group to which the belongs, and the discrimination performance is evaluated.
- the gene selection and discriminant formula are created by statistical test using all the samples, and the newly prepared sample is discriminated by the discriminant to improve accuracy, sensitivity, and specificity. It is also possible to calculate and evaluate the discrimination performance.
- the present invention relates to a polynucleotide for disease diagnosis useful for diagnosis and treatment of early pancreatic cancer or pancreatic cancer precursor lesion, a method for detecting early pancreatic cancer or pancreatic cancer precursor lesion using the polynucleotide, and the An early pancreatic cancer or pancreatic cancer precursor lesion detection kit and device containing nucleotides are provided.
- the base sequence represented by any of SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250 as described above, or the base sequence in which u of the base sequence is t, or a complement thereof One or more of the above polynucleotides based on the target sequence, and optionally the base sequence represented by any of SEQ ID NOs: 84 to 226, 230 to 245, 247, and 249, or u of the base sequence is t
- One or two or more of the above-mentioned polynucleotides based on the base sequence that is or its complementary sequence, and optionally the base sequence represented by any of SEQ ID NOs: 227 to 245, or u of the base sequence is t
- An arbitrary combination of one or two or more of the above polynucleotides based on a certain base sequence or its complementary sequence is used as a diagnostic gene set.
- the diagnosis in the specimen derived from patients with early stage pancreatic cancer or pancreatic cancer precursor lesions of class I whose diagnosis result of tissue diagnosis is, and specimens derived from class II healthy bodies and / or other cancers and / or benign diseases A discriminant is constructed using the expression level of the gene set.
- the subject from which the unknown specimen is derived includes early pancreatic cancer or pancreatic cancer precursor lesions, or early pancreatic cancer or pancreatic It is possible to recognize with no accuracy up to 100% that cancer precursor lesions are not included.
- pancreatic cancer without cancer in the organ who obtained informed consent (3 cases for IPMA low grade, 3 cases for IPMA high grade, 6 cases for IPMC), other than pancreas 13 patients with early pancreatic cancer with no cancer in their organs (3 cases of stage IIA and 10 cases of stage IIB) and 61 healthy subjects were treated with Venoject II vacuum blood collection tube VP-AS109K60 (Terumo Corporation) Serum was collected using each of the above to prepare a verification sample group.
- VP-AS109K60 Tuumo Corporation
- RNA extraction reagent liquid sample kit (Toray Industries, Inc., Japan) according to the protocol specified by the company.
- RNA obtained from the total 261 sera of 33 patients with pancreatic cancer precursor lesions, 184 healthy subjects, and 44 patients with early pancreatic cancer, including the above learning sample group and verification sample group as samples.
- 3D-Gene registered trademark
- miRNA was fluorescently labeled based on the protocol (ver 2.20) defined by the company.
- 3D-Gene Human miRNA Oligo chip (Toray Industries, Inc.) equipped with a probe having a sequence complementary to 2,555 miRNAs among miRNAs registered in miRBBase release 20 as an oligo DNA chip ) And hybridization and washing after hybridization under stringent conditions based on the protocol defined by the company.
- the DNA chip was scanned using a 3D-Gene (registered trademark) scanner (Toray Industries, Inc.), an image was acquired, and the fluorescence intensity was digitized with 3D-Gene (registered trademark) Extraction (Toray Industries, Inc.). The digitized fluorescence intensity is converted into a logarithmic value with a base of 2 to obtain the gene expression level, and the blank value is subtracted.
- the missing value is 0.1 from the logarithmic value of the minimum value of the gene expression level in each DNA chip. Replaced with the value obtained by subtracting.
- a comprehensive miRNA gene expression level was obtained for the serum of a total of 261 people including 33 pancreatic cancer precursor lesion patients, 184 healthy subjects, and 46 early pancreatic cancer patients.
- R language 3.0.2 R Development Core Team (2013). R: A language and environment for static computing. R Founding forstamping. URL http://www.R-project.org/.) And MASS package 7.3-30 (Venables, WN & Ripley, B. D. (2002) Modern Applied Statistics with S. Four S. D New York ISBN 0-387-95457-0).
- Omnibus http://www.ncbi.nlm.nih.gov/geo/ accession number: Data of 51 breast cancer patients, 35 prostate cancer patients, 26 prostate benign disease patients from GSE73002 data set 21 patients with pancreatic cancer precursor lesions of Reference Example 1 (4 cases with IPMA low grade) IPMA high grade 5 cases, IPMC 12 cases), early pancreatic cancer patients 31 (stage IIA 8 cases, stage IIB 22 cases), and 128 healthy subjects were used as a learning sample group.
- Example 1 ⁇ Selection of genetic markers using samples from the learning sample group and methods for evaluating early pancreatic cancer or pancreatic cancer precursor lesion discrimination performance of a single genetic marker using samples from the verification sample group>
- a genetic sample for discriminating early pancreatic cancer or pancreatic cancer precursor lesion as a positive control group and a healthy body as a negative control group is selected from the learning sample group, and the verification sample is independent of the learning sample group. The group specimens were examined.
- the miRNA expression levels of the learning sample group and the verification sample group obtained in the above reference example were combined and normalized by global normalization.
- a diagnostic gene was selected using a group of learning samples.
- 50% or more of the samples Only genes having a gene expression level of 2 6 or more were selected.
- a P obtained by a two-sided t-test assuming equal variance for each gene expression level The values were corrected by Bonferroni, and genes satisfying p ⁇ 0.01 were obtained as genetic markers used as explanatory variables in the discriminant equation, and are listed in Table 2.
- hsa-miR-6784-5p hsa-miR-1181, hsa-miR-671-5p, hsa-miR-6857-5p, hsa-miR-4276, hsa-miR-1914-3p, hsa -MiR-149-3p, hsa-miR-937-5p, hsa-miR-4675, hsa-miR-6695-5p, hsa-miR-4731-5p, hsa-miR-5090, hsa-miR-3620-5p Hsa-miR-6343-5p, hsa-miR-6717-5p, hsa-miR-6825-5p, hsa-miR-6638-5p, hsa-miR-6769a-5p, hsa-miR-4728-5p, hsa
- a discriminant for discriminating the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions was created by Fisher's discriminant analysis.
- the measured expression level of the polynucleotide comprising the nucleotide sequence represented by any one of SEQ ID NOs: 1 to 83 newly found is represented by Formula 2.
- a discriminant was created by inputting, and the calculated accuracy, sensitivity, and specificity are shown in Table 3.
- Table 4 shows the discriminant coefficients and constant terms at that time.
- the discriminant score obtained by using Fisher's discriminant analysis from the measured expression level of the base sequence represented by SEQ ID NO: 1 is used as a learning specimen group of pancreatic cancer precursor lesion patients (21), early pancreatic cancer patients ( 31)
- the learning sample group showed that the discrimination score of the early pancreatic cancer or pancreatic cancer precursor lesion group was significantly higher than the healthy subject group (see FIG. 2 left) Furthermore, this result could be reproduced even in the verification sample group (see the right side of FIG. 2).
- the measured gene expression level of the early pancreatic cancer or pancreatic cancer precursor lesion patient group is significantly lower (decreased) or higher than the healthy body group ( (Increased) results (Table 2) were obtained, and these results were verified in the verification sample group.
- the target for detection of early pancreatic cancer or pancreatic cancer precursor lesion in the verification sample group using the threshold (0) for discriminating both groups set in the learning sample group is used. The number was calculated to be 22 true positives, 52 true negatives, 9 false positives and 4 false negatives.
- the detection performance is 85.1% accuracy, sensitivity 84.6%, specificity 85. .2% was obtained.
- the detection performance of all the polynucleotides shown in SEQ ID NOs: 1 to 83 was calculated and listed in Table 3.
- each of the 26 polynucleotides having a sensitivity of 100% in the test sample group, 92.3%, 92.3%, 76.9%, 80.8%, 84.6%, 76.9%, 84.6%, 73.1%, 80.8%, 88.5%, 88.5%, 88.5%, 88.5%, 73.1%, 73.1%, 76.9%, 61.5%, 65.4%, 84.6%, 92.3%, 73.1%, 61.5%, 76.9%, 73.1%, 80.8%, 92.3% were shown (Table 3).
- the sensitivity of the existing marker CEA in the verification sample group was 20% and the sensitivity of CA19-9 was 68% (Table 5-2). 2, 3, 18, 12, 20, 1, 15, 50, 63, 72, 5, 24, 10, 52, 9, 11, 19, 39, 61, 7, 17, 22, 26, 74, 21, It was proved that the 26 polynucleotides consisting of the nucleotide sequence represented by 28 alone can discriminate early pancreatic cancer or pancreatic cancer precursor lesions with sensitivity higher than CA19-9 or similar sensitivity.
- Example 2 ⁇ Evaluation method A for early pancreatic cancer or pancreatic cancer precursor lesion discriminating ability by a combination of a plurality of genetic markers using a test sample group sample>
- a method for evaluating early pancreatic cancer or pancreatic cancer precursor lesion discrimination performance by combining the genetic markers selected in Example 1 was examined.
- pancreatic cancer precursor lesion patients 21
- early pancreatic cancer patients 311
- the learning sample group obtained a scatter plot in which the measured expression levels of the healthy subject group and the early pancreatic cancer or pancreatic cancer precursor lesion group were significantly separated.
- the test sample group obtained a scatter plot in which the measured expression levels of the healthy subject group and the early pancreatic cancer or pancreatic cancer precursor lesion group were significantly separated.
- Two other combinations, including at least one, also provide scatter plots that significantly separate gene expression measurements from healthy and early pancreatic cancer or pancreatic cancer precursor lesion groups, The result was verified in the verification sample group.
- a threshold 1.90 ⁇ hsa-miR-6784-5p + 1.72 ⁇ hsa-miR
- a threshold 1.90 ⁇ hsa-miR-6784-5p + 1.72 ⁇ hsa-miR
- the target number of detection of early pancreatic cancer or pancreatic cancer precursor lesions 52 true positives, 107 true negatives, 16 false positives, 16 false positives This was a negative example, and from these values, a detection performance of 90.3% accuracy, 98.1% sensitivity, and 87% specificity was obtained (see FIG. 3 left).
- SEQ ID NO indicates a combination of a plurality of used polynucleotides by SEQ ID NO (the same applies to the tables described later in this application).
- the measured expression level of a polynucleotide comprising the base sequences represented by SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 1 and SEQ ID NO: 3, SEQ ID NO: 1 and SEQ ID NO: 4, and SEQ ID NO: 1 and SEQ ID NO: 5
- sensitivities 92.3%, 88.5%, 84.6%, 88.5%, and 84.6% were shown in the verification sample group, respectively (Table 6).
- Table 7 shows combinations of two polynucleotides having a base sequence other than SEQ ID NO: 1.
- SEQ ID NO: 2 and 18 SEQ ID NO: 2 and 53, SEQ ID NO: 2 and 20, SEQ ID NO: 2 and 3, SEQ ID NO: 2 and 50, SEQ ID NO: 85 and 3, SEQ ID NO: 84 and 3, SEQ ID NO: 90 and 3, SEQ ID NO: 87 and 3, SEQ ID NO: 90 and 18, SEQ ID NO: 87 and 18, SEQ ID NO: 89 and 18, SEQ ID NO: 84 and 18, SEQ ID NO: 85 and 12, SEQ ID NO: 85 and 20, SEQ ID Nos.
- SEQ ID Nos. 90 and 20 SEQ ID Nos. 87 and 20, SEQ ID Nos. 87 and 15, SEQ ID Nos. 85 and 15, SEQ ID Nos. 2 and 15, SEQ ID Nos. 85 and 50, SEQ ID No.
- SEQ ID NO: 84 and 50 SEQ ID NO: 106 and 50, SEQ ID NO: 90 and 50, SEQ ID NO: 2 and 63, SEQ ID NO: 85 and 63, SEQ ID NO: 90 and 63, SEQ ID NO: 87 and 63, SEQ ID NO: 84 and 72, SEQ ID NO: 8 72, SEQ ID NO: 88 and 72, SEQ ID NO: 87 and 72, SEQ ID NO: 85 and 5, SEQ ID NO: 87 and 5, SEQ ID NO: 84 and 5, SEQ ID NO: 85 and 10, SEQ ID NO: 90 and 10, SEQ ID NO: 85 and 52 , SEQ ID NO: 88 and 52, SEQ ID NO: 87 and 52, SEQ ID NO: 98 and 52, SEQ ID NO: 84 and 52, SEQ ID NO: 87 and 9, SEQ ID NO: 85 and 9, SEQ ID NO: 117 and 9, SEQ ID NO: 88 and 9, SEQ ID NO: 87 and 11, SEQ ID NO: 85
- SEQ ID Nos. 85 and 74, SEQ ID Nos. 2 and 74, SEQ ID Nos. 87 and 74, SEQ ID Nos. 84 and 74, SEQ ID Nos. 88 and 74, SEQ ID Nos. 85 and 28, and SEQ ID Nos. 84 and 28 is a learning sample. Sensitivity of 95% or more for discriminating patients from early pancreatic cancer or pancreatic cancer precursor lesions from healthy subjects was shown in both the test group and the test sample group. Thus, there are 14,079 combinations of polynucleotide expression level measurements exceeding the sensitivity of existing marker CA19-9 (68% from Table 5-2) in the test sample group. All of the nucleotide sequences 1 to 226 shown in Table 2 obtained in 1 were used at least once.
- two combinations containing at least one expression level measurement value of any one of the polynucleotides represented by the nucleotide sequences represented by SEQ ID NOs: 1 to 226 have an early pancreatic sensitivity with a sensitivity exceeding CA19-9. It was proved to detect cancer or pancreatic cancer precursor lesions.
- the measured expression level of the polynucleotide comprising the nucleotide sequence represented by SEQ ID NOs: 1-226 is 3, 4, 5, 6, 7, 8, 9, 10, or A marker for detecting early pancreatic cancer or pancreatic cancer precursor lesions can be obtained with excellent sensitivity even when more polynucleotides are combined.
- the polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 226 selected in Example 1 were ranked in descending order of P values indicating statistical significance, and one was added from the top miRNA. Detection performance was calculated using a combination of one or more miRNAs.
- the sensitivity in the verification sample group was 69.2% for 2 miRNAs, 80.8% for 5 miRNAs, 92.3% for 10 miRNAs, 96.2% for 20 miRNAs, 100% with 100 miRNAs and 100% with 226 miRNAs. Since these sensitivities are higher than those of existing blood tumor markers, it was shown that even when a plurality of miRNAs are combined, they can be excellent markers for detecting early pancreatic cancer or pancreatic cancer precursor lesions.
- the combination of a plurality of miRNAs is not limited to addition in the order of statistical significance as described above, and any combination of a plurality of miRNAs can be used for detection of early pancreatic cancer or pancreatic cancer precursor lesions. Can be used.
- Table 2 Table 3
- Table 4 Table 5
- Table 6 Table 7
- Example 3 ⁇ Selection of genetic markers when all specimens are used and evaluation method of early pancreatic cancer or pancreatic cancer precursor lesion discrimination performance of the captured genetic markers>
- the samples of the learning sample group and the verification sample group used in Examples 1 and 2 above are integrated and all samples are used to select a genetic marker and its early pancreatic cancer or pancreatic cancer precursor lesion discrimination performance Evaluation was performed.
- the global expression level of miRNA for the serum of pancreatic cancer precursor lesion patients (33), early pancreatic cancer patients (44), and healthy subjects (184) obtained in the above Reference Example Normalization was performed by normalization.
- 50% or more of the samples should be 2 6 or more Only genes having the gene expression level of were selected.
- hsa-miR-6794-5p hsa-miR-6511a-5p, hsa-miR-6824-5p, hsa-miR-762, hsa-miR-6636- 3p, hsa-miR-6727-5p, hsa-miR-4737, hsa-miR-7777, hsa-miR-4484, hsa-miR-6515-3p, hsa-miR-373-5p, hsa-miR-4258, hsa-miR-4675, hsa-miR-3180, hsa-miR-6076, hsa-miR-1238-5p, hsa-miR-4463, hsa-miR-4486, and hsa-miR-4730 genes, related to these The nucleic acid sequence, hsa-m
- the polynucleotides shown in SEQ ID NOs: 227-245 also have significantly lower measured values for patients with early pancreatic cancer or pancreatic cancer precursor lesions compared to healthy groups ( Decrease) or high (increase) results (Table 8) were obtained, and these results could be verified in the validation sample group. Therefore, by using the measured values of the gene expression levels described in Table 8 alone or in combination, it is possible to discriminate newly obtained specimens by the methods described in Examples 1 and 2.
- Example 4 ⁇ Evaluation method for early pancreatic cancer or pancreatic cancer precursor lesion-specific discrimination performance by a combination of a plurality of genetic markers using a test sample group sample>
- a group of patients with precursors of pancreatic cancer lesion and a group of patients with early pancreatic cancer were positive by the same method as described in Example 1.
- control group healthy group, advanced pancreatic cancer patient group, biliary tract cancer patient group, breast cancer patient group, prostate cancer patient group, colon cancer patient group, stomach cancer patient group, esophageal cancer patient group, liver
- additional diagnostic gene markers were selected.
- the additional diagnostic genetic marker (SEQ ID NO: 246 to 247) selected in combination with the genetic marker selected in Example 1 can be used to provide discrimination performance specific to early pancreatic cancer or pancreatic cancer precursor lesions. The method of evaluation was examined.
- the miRNA expression levels of the learning sample group and the verification sample group obtained in Reference Example 2 above were combined and normalized by global normalization.
- the polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 250 newly discovered base sequences represented by SEQ ID NOs: 1 to 83, 227 to 229, 246, 248, and 250
- a discriminant that discriminates the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions by performing Fisher's discriminant analysis on 1 to 5 combinations including at least one expression level measurement value of any of the polynucleotides Built.
- pancreatic cancer precursor lesion patient group and early pancreatic cancer patient group as positive control group, healthy body group, advanced pancreatic cancer patient group, biliary tract cancer patient group, breast cancer patient group, prostate cancer patient Group, colon cancer patient group, stomach cancer patient group, esophageal cancer patient group, liver cancer patient group, pancreatic benign disease patient group, and prostate benign disease patient group as negative sample groups,
- the accuracy, sensitivity, and specificity in the verification sample group were calculated, and the discrimination performance of the selected polynucleotide was verified with an independent sample.
- polynucleotides consisting of the base sequence represented by the above SEQ ID NO (SEQ ID NO: 1 to 250 corresponding to the miRNA marker in Table 1) or its complementary sequence are present in early pancreatic cancer or pancreatic cancer precursor lesions In addition to providing relatively high accuracy, sensitivity, and specificity in determining the presence or absence, early pancreatic cancer or pancreatic cancer precursor lesions could be specifically identified from other cancers and benign diseases .
- the polynucleotide that can specifically bind to the target marker include, for example, SEQ ID NOs: 119, 12, 28, 105, 137, 121, 109, 87, 5, 140, 106, 2, 175, 90, 237, 247, 103.
- a polynucleotide comprising a complementary sequence thereof Among the combinations of a plurality of polynucleotides selected from the group (cancer type-specific polynucleotide group 1), preferably included in the cancer type-specific polynucleotide group 1, preferably SEQ ID NOs: 119, 12, 28, 105, 137, 121, 109, 87, 5, 140, 106, 2, 175, 90, 237, and 247 nucleotide sequences Or in a combination comprising at least one polynucleotide selected from the group consisting of polynucleotides consisting of complementary sequences thereof (cancer type-specific polynucleotide group 2), early pancreatic cancer or pancreatic cancer with high accuracy Precursor lesions could be specifically distinguished from other cancers and benign diseases.
- the number of combinations of the above-mentioned cancer species-specific polynucleotides is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more.
- the number of polynucleotides can be combined, but the discrimination accuracy was 92% or more or 95% or more in the combination of 4 or more.
- the probe used for the measurement is a nucleic acid as defined above that can specifically bind to each polynucleotide as a target marker.
- Table 9-1 shows the discrimination results when measurement was performed using a polynucleotide consisting of the base sequence represented by SEQ ID NO: 12 or a complementary sequence thereof as a target marker.
- the accuracy was 82.6% in the learning sample group and the accuracy was 82% in the verification sample group.
- the accuracy is 87% in the learning sample group and the accuracy in the verification sample group. 88%.
- the accuracy when measurement is performed using three combinations including one polynucleotide consisting of the base sequence represented by SEQ ID NO: 12 or a complementary sequence thereof, the accuracy is 91.4% in the learning sample group, and the verification sample group The accuracy was 86.6%.
- the accuracy when measurement is performed using four combinations including one polynucleotide consisting of the base sequence represented by SEQ ID NO: 12 or a complementary sequence thereof, the accuracy is 95.6% in the learning sample group, and the verification sample group The accuracy was 95.1%.
- the maximum accuracy is 98.8% in the learning sample group.
- the sample group showed a maximum accuracy of 98.9%.
- Table 9-2 shows the discrimination results when measurement was performed using a polynucleotide consisting of the base sequence represented by SEQ ID NO: 28 or a complementary sequence thereof as a target marker.
- the accuracy was 81.6% in the learning sample group and the accuracy was 81.7% in the verification sample group.
- the test sample group has an accuracy of 84.9%. The accuracy was 85.6%.
- the accuracy when measurement is performed using three combinations including one polynucleotide consisting of the base sequence represented by SEQ ID NO: 28 or a complementary sequence thereof, the accuracy is 88.8% in the learning sample group, and the verification sample group The accuracy was 86.3%. Further, for example, when measurement is performed using four combinations including one polynucleotide consisting of the base sequence represented by SEQ ID NO: 28 or a complementary sequence thereof, the accuracy is 92.4% in the learning sample group, and the verification sample group The accuracy was 93.6%.
- the maximum accuracy is 97.7% in the learning sample group.
- the highest accuracy was 98.6% in the sample group.
- Table 9-3 shows the discrimination results when measurement was performed using a polynucleotide consisting of the base sequence represented by SEQ ID NO: 5 or a complementary sequence thereof as a target marker.
- the accuracy was 84% in the learning sample group and the accuracy 87% in the verification sample group.
- the test sample group has an accuracy of 87.9%. The accuracy was 88.4%.
- the accuracy when measurement is performed using three combinations including one polynucleotide consisting of the base sequence represented by SEQ ID NO: 5 or its complementary sequence, the accuracy is 90.4% in the learning sample group, and the verification sample group The accuracy was 90.5%. Further, for example, when measurement is performed using four combinations including one polynucleotide consisting of the base sequence represented by SEQ ID NO: 5 or a complementary sequence thereof, the accuracy of the test sample group is 93.2%. The accuracy was 93.7%. Further, for example, when measurement is performed using five combinations including one polynucleotide consisting of the nucleotide sequence represented by SEQ ID NO: 5 or its complementary sequence, the maximum accuracy is 97.7% in the learning sample group. The highest accuracy in the sample group was 98.2%.
- Table 9-4 shows the discrimination results when measurement was performed using a polynucleotide consisting of the base sequence represented by SEQ ID NO: 2 or a complementary sequence thereof as a target marker.
- the accuracy was 86.8% in the learning sample group and the accuracy was 90.5% in the verification sample group.
- the test sample group has an accuracy of 88.4%. The accuracy was 90.1%.
- the accuracy when measurement is performed using three combinations including one polynucleotide consisting of the base sequence represented by SEQ ID NO: 2 or a complementary sequence thereof, the accuracy is 90.9% in the learning sample group, and the verification sample group The accuracy was 92.6%.
- the accuracy when measurement is performed using four combinations including one polynucleotide consisting of the base sequence represented by SEQ ID NO: 2 or its complementary sequence, the accuracy is 93% in the learning sample group and the accuracy in the verification sample group It was 92.6%.
- the maximum accuracy is 97.7% in the learning sample group. The highest accuracy in the sample group was 98.2%.
- Table 9-5 shows the discrimination results when measurement was performed using a polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 12 and 28 or a complementary sequence thereof as a target marker.
- the accuracy is 90% in the learning sample group and the accuracy is 92.6% in the verification sample group. showed that.
- the accuracy is 92.3% in the learning sample group, and the verification sample group The accuracy was 93.3%.
- the accuracy is 93.9% in the learning sample group, and the verification sample group The accuracy was 93.7%.
- the maximum accuracy is 97.9% in the learning sample group.
- the highest accuracy in the sample group was 97.9%.
- Table 9-6 shows the discrimination results when measurement was performed using a polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 12 and 5 or a complementary sequence thereof as a target marker.
- the accuracy is 91.2% in the learning sample group and the accuracy is 89.89 in the verification sample group. 4%.
- the accuracy is 93% in the learning sample group and the accuracy in the verification sample group It was 92.6%.
- the accuracy is 95.1% in the learning sample group, and the verification sample group The accuracy was 93%.
- the maximum accuracy is 98.1% in the learning sample group.
- the highest accuracy in the sample group was 97.9%.
- Table 9-7 shows the discrimination results when measurement was performed using a polynucleotide consisting of the base sequence represented by SEQ ID NOs: 12 and 2 or a complementary sequence thereof as a target marker.
- the accuracy is 91.2% in the learning sample group and the accuracy is 90. 0 in the verification sample group. 1%.
- the accuracy is 93.9% in the learning sample group, and the verification sample group The accuracy was 92.6%.
- the accuracy when measurement is performed using four combinations including a polynucleotide consisting of the nucleotide sequences represented by SEQ ID NOs: 12 and 2 or their complementary sequences, the accuracy of 94.6% in the learning sample group and the verification sample group The accuracy was 93.3%.
- the maximum accuracy is 98.1% in the learning sample group.
- the highest accuracy in the sample group was 97.9%.
- Table 9-8 shows the discrimination results when measurement was performed using a polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 5 and 2 or a complementary sequence thereof as a target marker.
- the accuracy is 89.8% in the learning sample group and the accuracy is 92. 2 in the verification sample group. 3%.
- the accuracy when measurement is performed using three combinations including the nucleotide sequence represented by SEQ ID NOs: 5 and 2 or a polynucleotide comprising a complementary sequence thereof, the accuracy is 92.1% in the learning sample group, and the verification sample group The accuracy was 94%.
- the accuracy when measurement is performed using four combinations including the nucleotide sequences represented by SEQ ID NOs: 5 and 2 or a polynucleotide comprising a complementary sequence thereof, the accuracy is 93.9% in the learning sample group, and the verification sample group The accuracy was 95.1%.
- the maximum accuracy is 97.2% in the learning sample group.
- the highest accuracy in the sample group was 97.9%.
- Table 9-9 shows the discrimination results when measured using the polynucleotide consisting of the base sequence represented by SEQ ID NOs: 12, 28 and 5 or a complementary sequence thereof as a target marker.
- the accuracy is 93.3% in the learning sample group, and the verification sample group The accuracy was 94.4%.
- the accuracy when measurement is performed using four combinations including a polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 12, 28 and 5 or a complementary sequence thereof, the accuracy of 94.6% in the learning sample group In the verification sample group, the accuracy was 96.5%. Further, for example, when measurement is performed using 5 combinations including a polynucleotide consisting of the nucleotide sequence represented by SEQ ID NOs: 12, 28 and 5 or a complementary sequence thereof, the accuracy is 97.5% in the learning sample group In the verification sample group, the accuracy was 96.8%.
- Example 5 ⁇ Evaluation method of early pancreatic cancer or pancreatic cancer precursor lesion discriminating ability by a combination of a plurality of genetic markers using test sample group>
- Example 2 it was shown that the discrimination performance was improved by combining a plurality of gene markers selected in Example 1 as compared with the case of using one gene marker. Therefore, in this example, can a gene marker not selected in Example 1 be combined with the gene marker selected in Example 1 to obtain high performance for distinguishing early pancreatic cancer or pancreatic cancer precursor lesions? investigated.
- a gene having a gene expression level of 2 6 or more in 50% or more of specimens in either the early pancreatic cancer of the learning specimen group and the healthy body group of the pancreatic cancer patient group or the learning specimen group As a gene with statistical significance for discriminating between early pancreatic cancer or pancreatic cancer precursor lesion group and healthy body group, it is obtained by two-sided t-test assuming equal variance for each gene expression level When the P value was Bonferroni corrected and genes satisfying p ⁇ 0.05 were examined, 248 genes including 226 selected in Example 1 were found.
- 30,876 Fisher discriminant analyzes using one or two of the 248 genes described above, and a discriminant that discriminates the presence or absence of early pancreatic cancer or pancreatic cancer precursor lesions are constructed and selected. The discrimination performance of the combination of one or two genes was verified by the same method as in Example 2.
- Table 10 shows a part of gene combinations that showed an accuracy of 85% or more in both the learning sample group and the verification sample group.
- the newly found polynucleotide consisting of the base sequence represented by SEQ ID NOs: 248 to 250 includes at least two combinations including any of the polynucleotides consisting of the base sequence represented by SEQ ID NOs: 1 to 226
- early pancreatic cancer or pancreatic cancer precursor lesions and healthy bodies were distinguished with high discrimination performance.
- the polynucleotide comprising the nucleotide sequence represented by SEQ ID NOs: 248 to 250 is SEQ ID NO: 2, 3, 18, 12, 20, 1, 15, 50, 63, 72, 5, 24, 10 , 52, 9, 11, 19, 39, 61, 7, 17, 22, 26, 74, 21, 28, and used as a combination of at least two containing any of the polynucleotides consisting of the base sequences represented by In both the learning sample group and the verification sample group, it was possible to show a discrimination accuracy of 85% or higher between early pancreatic cancer or pancreatic cancer precursor lesions and healthy bodies.
- Hsa-miR-4294, hsa-miR-6636-3p, hsa-miR-4530, and hsa-miR-6880-5p, hsa-miR-4294 (SEQ ID NO: 125) included in the present invention An early pancreatic cancer or pancreatic cancer precursor lesion for a combination of one or more miRNAs selected from hsa-miR-6636-3p (SEQ ID NO: 231) and hsa-miR-6880-5p (SEQ ID NO: 219) The discriminating performance against was evaluated.
- the combination of polynucleotides consisting of the base sequences represented by SEQ ID NOs: 219, 125 and 231 or their complementary sequences showed excellent accuracy of 93% in both the learning sample group and the verification sample group.
- the sensitivity of the learning sample group is 50%
- the specificity is 94.7%
- the sensitivity of the verification sample group is 72.7%
- the specificity is 93.8%. (Table 11).
- SEQ ID NOS: 119, 12, 28, 105, 137, 121, 109, 87, 5, 140, 106, 2, 175, 90 When measured using, for example, a combination of three polynucleotides, including at least one polynucleotide selected from the group consisting of polynucleotides consisting of the nucleotide sequences represented by 237 and 247 or a complementary sequence thereof, Sensitivity is 100% at the highest in the learning sample group, 88.7% at the lowest, specificity is 93.2% at the highest, and 88.8% is the lowest.
- a combination of two or more, preferably three or more, more preferably four or more or five or more polynucleotides comprising at least one polynucleotide selected from the group consisting of: It shows a high discrimination performance exceeding the combination of blood miRNA markers and can be said to be an excellent diagnostic marker.
- a combination of polynucleotides consisting of the base sequences represented by SEQ ID NOs: 813 to 817 or a complementary sequence thereof has a sensitivity of 63.6% in the learning sample group, a specificity of 74.5%, and a sensitivity of 54.5% in the verification sample group The specificity was 74.7% (Table 12).
- SEQ ID NOS: 119, 12, 28, 105, 137, 121, 109, 87, 5, 140, 106, 2, 175, Measured using, for example, a combination of five polynucleotides, including at least one polynucleotide selected from the group consisting of polynucleotides consisting of the nucleotide sequences represented by 90, 237, and 247 or their complementary sequences.
- the maximum sensitivity is 100% in the learning sample group, the minimum is 94.3%, the specificity is the maximum is 98.6%, the minimum is 96.9%, and the sensitivity is the maximum in the verification sample group is 100%.
- nucleotide sequence represented by SEQ ID NOs: 119, 12, 28, 105, 137, 121, 109, 87, 5, 140, 106, 2, 175, 90, 237, and 247 or a complementary sequence thereof A combination of two or more, preferably three or more, more preferably four or more or five or more polynucleotides comprising at least one polynucleotide selected from the group consisting of: And it shows high discrimination performance exceeding the combination of blood miRNA markers for pancreatic cancer precursor lesions and can be said to be an excellent diagnostic marker.
- pancreatic cancer or pancreatic cancer precursor lesions can be detected more sensitively and specifically than existing tumor markers. It is possible to make an early decision on the treatment and removal of the cancerous part by surgery, and as a result, it is possible to improve the 5-year survival rate and reduce the recurrence rate.
- early pancreatic cancer or pancreatic cancer precursor lesions can be detected in a subject with considerably higher sensitivity, specificity, and accuracy as compared with conventional methods. Enables early detection, diagnosis and treatment of lesions.
- early pancreatic cancer or pancreatic cancer precursor lesions can be detected minimally invasively using the blood of the subject, early pancreatic cancer or pancreatic cancer precursor lesions can be determined easily, quickly and inexpensively. It becomes possible to do.
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Abstract
Description
すなわち、本発明は、以下の特徴を有する。
(1)早期膵がん又は膵がん前駆病変マーカーである、miR-6784-5p、miR-1181、miR-671-5p、miR-6857-5p、miR-4276、miR-1914-3p、miR-149-3p、miR-937-5p、miR-4675、miR-6795-5p、miR-4731-5p、miR-5090、miR-3620-5p、miR-1343-5p、miR-6717-5p、miR-6825-5p、miR-6738-5p、miR-6769a-5p、miR-4728-5p、miR-652-5p、miR-4257、miR-6785-5p、miR-7110-5p、miR-6887-5p、miR-887-3p、miR-1228-5p、miR-5572、miR-6782-5p、miR-4298、miR-6786-5p、miR-5010-5p、miR-6087、miR-6765-5p、miR-6732-5p、miR-6787-5p、miR-6737-5p、miR-128-2-5p、miR-4270、miR-6861-5p、miR-6756-5p、miR-1229-5p、miR-6891-5p、miR-6848-5p、miR-1237-5p、miR-30c-1-3p、miR-1233-5p、miR-211-3p、miR-4758-5p、miR-614、miR-6746-5p、miR-1915-5p、miR-4688、miR-3917、miR-5787、miR-4632-5p、miR-6126、miR-135a-3p、miR-8063、miR-5698、miR-6089、miR-498、miR-296-3p、miR-4419b、miR-6802-5p、miR-6829-5p、miR-6803-5p、miR-1199-5p、miR-6840-3p、miR-6752-5p、miR-6798-5p、miR-6131、miR-4667-5p、miR-6510-5p、miR-4690-5p、miR-920、miR-23b-3p、miR-4448、miR-2110、miR-4706、miR-7845-5p、miR-6808-5p、miR-4447、miR-6869-5p、miR-6794-5p、miR-6511a-5p、miR-6824-5p、miR-6766-3p、miR-6511a-5p、及び、miR-6749-5pからなる群から選択される少なくとも1つのポリヌクレオチドと特異的に結合可能な核酸を含む、早期膵がん又は膵がん前駆病変の検出用キット。
(a)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(b)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列を含むポリヌクレオチド、
(c)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(d)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列を含むポリヌクレオチド、及び
(e)上記(a)~(d)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択されるポリヌクレオチドである、(1)又は(2)に記載のキット。
(f)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(g)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列を含むポリヌクレオチド、
(h)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(i)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列を含むポリヌクレオチド、及び
(j)前記(f)~(i)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択されるポリヌクレオチドである、(4)又は(5)に記載のキット。
(a)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(b)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列を含むポリヌクレオチド、
(c)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(d)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列を含むポリヌクレオチド、及び
(e)上記(a)~(d)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択されるポリヌクレオチドである、(7)又は(8)に記載のデバイス。
(f)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(g)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列を含むポリヌクレオチド、
(h)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(i)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列を含むポリヌクレオチド、及び
(j)上記(f)~(i)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択されるポリヌクレオチドである、(10)又は(11)に記載のデバイス。
本明細書中で使用する用語は、以下の定義を有する。
1.早期膵がん又は膵がん前駆病変の標的核酸
本発明の上記定義の早期膵がん又は膵がん前駆病変検出用の核酸プローブ又はプライマーを使用して、早期膵がん又は膵がん前駆病変又は早期膵がん又は膵がん前駆病変細胞の存在及び/又は不存在を検出するための、早期膵がん又は膵がん前駆病変マーカーとしての主要な標的核酸には、hsa-miR-6784-5p、hsa-miR-1181、hsa-miR-671-5p、hsa-miR-6857-5p、hsa-miR-4276、hsa-miR-1914-3p、hsa-miR-149-3p、hsa-miR-937-5p、hsa-miR-4675、hsa-miR-6795-5p、hsa-miR-4731-5p、hsa-miR-5090、hsa-miR-3620-5p、hsa-miR-1343-5p、hsa-miR-6717-5p、hsa-miR-6825-5p、hsa-miR-6738-5p、hsa-miR-6769a-5p、hsa-miR-4728-5p、hsa-miR-652-5p、hsa-miR-4257、hsa-miR-6785-5p、hsa-miR-7110-5p、hsa-miR-6887-5p、hsa-miR-887-3p、hsa-miR-1228-5p、hsa-miR-5572、hsa-miR-6782-5p、hsa-miR-4298、hsa-miR-6786-5p、hsa-miR-5010-5p、hsa-miR-6087、hsa-miR-6765-5p、hsa-miR-6732-5p、hsa-miR-6787-5p、hsa-miR-6737-5p、hsa-miR-128-2-5p、hsa-miR-4270、hsa-miR-6861-5p、hsa-miR-6756-5p、hsa-miR-1229-5p、hsa-miR-6891-5p、hsa-miR-6848-5p、hsa-miR-1237-5p、hsa-miR-30c-1-3p、hsa-miR-1233-5p、hsa-miR-211-3p、hsa-miR-4758-5p、hsa-miR-614、hsa-miR-6746-5p、hsa-miR-1915-5p、hsa-miR-4688、hsa-miR-3917、hsa-miR-5787、hsa-miR-4632-5p、hsa-miR-6126、hsa-miR-135a-3p、hsa-miR-8063、hsa-miR-5698、hsa-miR-6089、hsa-miR-498、hsa-miR-296-3p、hsa-miR-4419b、hsa-miR-6802-5p、hsa-miR-6829-5p、hsa-miR-6803-5p、hsa-miR-1199-5p、hsa-miR-6840-3p、hsa-miR-6752-5p、hsa-miR-6798-5p、hsa-miR-6131、hsa-miR-4667-5p、hsa-miR-6510-5p、hsa-miR-4690-5p、hsa-miR-920、hsa-miR-23b-3p、hsa-miR-4448、hsa-miR-2110、hsa-miR-4706、hsa-miR-7845-5p、hsa-miR-6808-5p、hsa-miR-4447、hsa-miR-6869-5p、hsa-miR-6794-5p、hsa-miR-6511a-5p、hsa-miR-6824-5p、hsa-miR-6766-3p、hsa-miR-6511a-5p、及び、hsa-miR-6749-5pからなる群から選択される少なくとも1つのmiRNAが含まれる。
本発明においては、上記の早期膵がん又は膵がん前駆病変マーカーとしての標的核酸に特異的に結合可能な核酸を、早期膵がん又は膵がん前駆病変を検出又は診断するための核酸、例えば核酸プローブ又はプライマーとして用いることができる。
(a)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(b)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列を含むポリヌクレオチド、
(c)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(d)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、に相補的な塩基配列を含むポリヌクレオチド、並びに、
(e)前記(a)~(d)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド。
(f)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(g)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列を含むポリヌクレオチド、
(h)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(i)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、に相補的な塩基配列を含むポリヌクレオチド、並びに、
(j)前記(f)~(i)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド。
本発明はまた、早期膵がん又は膵がん前駆病変マーカーである標的核酸を測定するための、本発明において核酸プローブ又はプライマーとして使用可能なポリヌクレオチド(これには、変異体、断片、又は誘導体を含みうる。)の1つ又は複数を含む早期膵がん又は膵がん前駆病変検出用のキット又はデバイスを提供する。
hsa-miR-6784-5p、hsa-miR-1181、hsa-miR-671-5p、hsa-miR-6857-5p、hsa-miR-4276、hsa-miR-1914-3p、hsa-miR-149-3p、hsa-miR-937-5p、hsa-miR-4675、hsa-miR-6795-5p、hsa-miR-4731-5p、hsa-miR-5090、hsa-miR-3620-5p、hsa-miR-1343-5p、hsa-miR-6717-5p、hsa-miR-6825-5p、hsa-miR-6738-5p、hsa-miR-6769a-5p、hsa-miR-4728-5p、hsa-miR-652-5p、hsa-miR-4257、hsa-miR-6785-5p、hsa-miR-7110-5p、hsa-miR-6887-5p、hsa-miR-887-3p、hsa-miR-1228-5p、hsa-miR-5572、hsa-miR-6782-5p、hsa-miR-4298、hsa-miR-6786-5p、hsa-miR-5010-5p、hsa-miR-6087、hsa-miR-6765-5p、hsa-miR-6732-5p、hsa-miR-6787-5p、hsa-miR-6737-5p、hsa-miR-128-2-5p、hsa-miR-4270、hsa-miR-6861-5p、hsa-miR-6756-5p、hsa-miR-1229-5p、hsa-miR-6891-5p、hsa-miR-6848-5p、hsa-miR-1237-5p、hsa-miR-30c-1-3p、hsa-miR-1233-5p、hsa-miR-211-3p、hsa-miR-4758-5p、hsa-miR-614、hsa-miR-6746-5p、hsa-miR-1915-5p、hsa-miR-4688、hsa-miR-3917、hsa-miR-5787、hsa-miR-4632-5p、hsa-miR-6126、hsa-miR-135a-3p、hsa-miR-8063、hsa-miR-5698、hsa-miR-6089、hsa-miR-498、hsa-miR-296-3p、hsa-miR-4419b、hsa-miR-6802-5p、hsa-miR-6829-5p、hsa-miR-6803-5p、hsa-miR-1199-5p、hsa-miR-6840-3p、hsa-miR-6752-5p、hsa-miR-6798-5p、hsa-miR-6131、hsa-miR-4667-5p、hsa-miR-6510-5p、hsa-miR-4690-5p、hsa-miR-920、hsa-miR-23b-3p、hsa-miR-4448、hsa-miR-2110、hsa-miR-4706、hsa-miR-7845-5p、hsa-miR-6808-5p、hsa-miR-4447、hsa-miR-6869-5p、hsa-miR-6794-5p、hsa-miR-6511a-5p、hsa-miR-6824-5p、hsa-miR-6766-3p、hsa-miR-6511a-5p、及び、hsa-miR-6749-5p。
hsa-miR-1908-5p、hsa-miR-6729-5p、hsa-miR-5195-3p、hsa-miR-638、hsa-miR-6125、hsa-miR-3178、hsa-miR-3196、hsa-miR-8069、hsa-miR-4723-5p、hsa-miR-4746-3p、hsa-miR-4689、hsa-miR-6816-5p、hsa-miR-6757-5p、hsa-miR-7109-5p、hsa-miR-6724-5p、hsa-miR-1225-3p、hsa-miR-6875-5p、hsa-miR-7108-5p、hsa-miR-4508、hsa-miR-6085、hsa-miR-6779-5p、hsa-miR-642a-3p、hsa-miR-4695-5p、hsa-miR-7847-3p、hsa-miR-3197、hsa-miR-6769b-5p、hsa-miR-7641、hsa-miR-187-5p、hsa-miR-3185、hsa-miR-2861、hsa-miR-3940-5p、hsa-miR-1203、hsa-miR-615-5p、hsa-miR-4787-5p、hsa-miR-1343-3p、hsa-miR-6813-5p、hsa-miR-1225-5p、hsa-miR-602、hsa-miR-4488、hsa-miR-125a-3p、hsa-miR-5100、hsa-miR-4294、hsa-miR-1231、hsa-miR-6765-3p、hsa-miR-4442、hsa-miR-718、hsa-miR-6780b-5p、hsa-miR-6090、hsa-miR-6845-5p、hsa-miR-4741、hsa-miR-4467、hsa-miR-4707-5p、hsa-miR-4271、hsa-miR-4673、hsa-miR-3184-5p、hsa-miR-1469、hsa-miR-4640-5p、hsa-miR-663a、hsa-miR-6791-5p、hsa-miR-6826-5p、hsa-miR-4433b-3p、hsa-miR-1915-3p、hsa-miR-4417、hsa-miR-4449、hsa-miR-4707-3p、hsa-miR-3180-3p、hsa-miR-5585-3p、hsa-miR-1268a、hsa-miR-8072、hsa-miR-296-5p、hsa-miR-204-3p、hsa-miR-4454、hsa-miR-6722-3p、hsa-miR-1290、hsa-miR-3622a-5p、hsa-miR-939-5p、hsa-miR-675-5p、hsa-miR-3131、hsa-miR-4648、hsa-miR-1268b、hsa-miR-6741-5p、hsa-miR-6893-5p、hsa-miR-3162-5p、hsa-miR-642b-3p、hsa-miR-4734、hsa-miR-150-3p、hsa-miR-8089、hsa-miR-6805-3p、hsa-miR-7113-3p、hsa-miR-6850-5p、hsa-miR-6799-5p、hsa-miR-6768-5p、hsa-miR-92b-5p、hsa-miR-3679-5p、hsa-miR-4792、hsa-miR-3656、hsa-miR-92a-2-5p、hsa-miR-4466、hsa-miR-4513、hsa-miR-6781-5p、hsa-miR-4649-5p、hsa-miR-6775-5p、hsa-miR-4651、hsa-miR-3195、hsa-miR-6726-5p、hsa-miR-6872-3p、hsa-miR-371a-5p、hsa-miR-6777-5p、hsa-miR-6789-5p、hsa-miR-7975、hsa-miR-6821-5p、hsa-miR-4534、hsa-miR-619-5p、hsa-miR-7107-5p、hsa-miR-1228-3p、hsa-miR-6774-5p、hsa-miR-6805-5p、hsa-miR-23a-3p、hsa-miR-4665-5p、hsa-miR-4505、hsa-miR-4638-5p、hsa-miR-24-3p、hsa-miR-3135b、hsa-miR-4745-5p、hsa-miR-128-1-5p、hsa-miR-4476、hsa-miR-4687-3p、hsa-miR-3665、hsa-miR-6806-5p、hsa-miR-3937、hsa-miR-711、hsa-miR-3141、hsa-miR-3188、hsa-miR-4281、hsa-miR-5196-5p、hsa-miR-6880-5p、hsa-miR-3960、hsa-miR-3648、hsa-miR-6721-5p、hsa-miR-4492、hsa-miR-744-5p、hsa-miR-7704、hsa-miR-4749-5p、hsa-miR-762、hsa-miR-6836-3p、hsa-miR-6727-5p、hsa-miR-4739、hsa-miR-7977、hsa-miR-4484、hsa-miR-6515-3p、hsa-miR-373-5p、hsa-miR-4258、hsa-miR-4674、hsa-miR-3180、hsa-miR-6076、hsa-miR-1238-5p、hsa-miR-4463、hsa-miR-4486、hsa-miR-4730、hsa-miR-4286、及び、hsa-miR-4739。
(1)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列においてuがtである塩基配列又はその相補的配列において、15以上、17以上又は19以上の連続した塩基を含むポリヌクレオチド。
(2)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列においてuがtである塩基配列又はその相補的配列において、15以上、17以上又は19以上の連続した塩基を含むポリヌクレオチド。
(1)配列番号2と18(マーカー:hsa-miR-1181とhsa-miR-6769a-5p)の組み合わせ
(2)配列番号2と53(マーカー:hsa-miR-1181とhsa-miR-3917)の組み合わせ
(3)配列番号2と20(マーカー:hsa-miR-1181とhsa-miR-652-5p)の組み合わせ
(4)配列番号2と3(マーカー:hsa-miR-1181とhsa-miR-671-5p)の組み合わせ
(5)配列番号2と50(マーカー:hsa-miR-1181とhsa-miR-6746-5p)の組み合わせ
(1)配列番号85と3(マーカー:hsa-miR-6729-5pとhsa-miR-671-5p)の組み合わせ
(2)配列番号84と3(マーカー:hsa-miR-1908-5pとhsa-miR-671-5p)の組み合わせ
(3)配列番号90と3(マーカー:hsa-miR-3196とhsa-miR-671-5p)の組み合わせ
(4)配列番号87と3(マーカー:hsa-miR-638とhsa-miR-671-5p)の組み合わせ
(5)配列番号3と137(マーカー:hsa-miR-671-5pとhsa-miR-4673)の組み合わせ
(1)配列番号90と18(マーカー:hsa-miR-3196とhsa-miR-6769a-5p)の組み合わせ
(2)配列番号87と18(マーカー:hsa-miR-638とhsa-miR-6769a-5p)の組み合わせ
(3)配列番号89と18(マーカー:hsa-miR-3178とhsa-miR-6769a-5p)の組み合わせ
(4)配列番号18と137(マーカー:hsa-miR-6769a-5pとhsa-miR-4673)の組み合わせ
(5)配列番号84と18(マーカー:hsa-miR-1908-5pとhsa-miR-6769a-5p)の組み合わせ
(1)配列番号86と12(マーカー:hsa-miR-5195-3pとhsa-miR-5090)の組み合わせ
(2)配列番号109と12(マーカー:hsa-miR-6769b-5pとhsa-miR-5090)の組み合わせ
(3)配列番号85と12(マーカー:hsa-miR-6729-5pとhsa-miR-5090)の組み合わせ
(4)配列番号88と12(マーカー:hsa-miR-6125とhsa-miR-5090)の組み合わせ
(5)配列番号105と12(マーカー:hsa-miR-642a-3pとhsa-miR-5090)の組み合わせ
(1)配列番号85と20(マーカー:hsa-miR-6729-5pとhsa-miR-652-5p)の組み合わせ
(2)配列番号84と20(マーカー:hsa-miR-1908-5pとhsa-miR-652-5p)の組み合わせ
(3)配列番号106と20(マーカー:hsa-miR-4695-5pとhsa-miR-652-5p)の組み合わせ
(4)配列番号90と20(マーカー:hsa-miR-3196とhsa-miR-652-5p)の組み合わせ
(5)配列番号87と20(マーカー:hsa-miR-638とhsa-miR-652-5p)の組み合わせ
(1)配列番号85と1(マーカー:hsa-miR-6729-5pとhsa-miR-6784-5p)の組み合わせ
(2)配列番号87と1(マーカー:hsa-miR-638とhsa-miR-6784-5p)の組み合わせ
(3)配列番号88と1(マーカー:hsa-miR-6125とhsa-miR-6784-5p)の組み合わせ
(4)配列番号86と1(マーカー:hsa-miR-5195-3pとhsa-miR-6784-5p)の組み合わせ
(5)配列番号1と3(マーカー:hsa-miR-6784-5pとhsa-miR-671-5p)の組み合わせ
(1)配列番号87と15(マーカー:hsa-miR-638とhsa-miR-6717-5p)の組み合わせ
(2)配列番号85と15(マーカー:hsa-miR-6729-5pとhsa-miR-6717-5p)の組み合わせ
(3)配列番号2と15(マーカー:hsa-miR-1181とhsa-miR-6717-5p)の組み合わせ
(4)配列番号88と15(マーカー:hsa-miR-6125とhsa-miR-6717-5p)の組み合わせ
(5)配列番号15と137(マーカー:hsa-miR-6717-5pとhsa-miR-4673)の組み合わせ
(1)配列番号85と50(マーカー:hsa-miR-6729-5pとhsa-miR-6746-5p)の組み合わせ
(2)配列番号87と50(マーカー:hsa-miR-638とhsa-miR-6746-5p)の組み合わせ
(3)配列番号84と50(マーカー:hsa-miR-1908-5pとhsa-miR-6746-5p)の組み合わせ
(4)配列番号106と50(マーカー:hsa-miR-4695-5pとhsa-miR-6746-5p)の組み合わせ
(5)配列番号90と50(マーカー:hsa-miR-3196とhsa-miR-6746-5p)の組み合わせ
(1)配列番号2と63(マーカー:hsa-miR-1181とhsa-miR-4419b)の組み合わせ
(2)配列番号85と63(マーカー:hsa-miR-6729-5pとhsa-miR-4419b)の組み合わせ
(3)配列番号90と63(マーカー:hsa-miR-3196とhsa-miR-4419b)の組み合わせ
(4)配列番号84と63(マーカー:hsa-miR-1908-5pとhsa-miR-4419b)の組み合わせ
(5)配列番号87と63(マーカー:hsa-miR-638とhsa-miR-4419b)の組み合わせ
(1)配列番号84と72(マーカー:hsa-miR-1908-5pとhsa-miR-4667-5p)の組み合わせ
(2)配列番号85と72(マーカー:hsa-miR-6729-5pとhsa-miR-4667-5p)の組み合わせ
(3)配列番号88と72(マーカー:hsa-miR-6125とhsa-miR-4667-5p)の組み合わせ
(4)配列番号87と72(マーカー:hsa-miR-638とhsa-miR-4667-5p)の組み合わせ
(5)配列番号93と72(マーカー:hsa-miR-4746-3pとhsa-miR-4667-5p)の組み合わせ
(1)配列番号94と5(マーカー:hsa-miR-4689とhsa-miR-4276)の組み合わせ
(2)配列番号85と5(マーカー:hsa-miR-6729-5pとhsa-miR-4276)の組み合わせ
(3)配列番号87と5(マーカー:hsa-miR-638とhsa-miR-4276)の組み合わせ
(4)配列番号5と107(マーカー:hsa-miR-4276とhsa-miR-7847-3p)の組み合わせ
(5)配列番号84と5(マーカー:hsa-miR-1908-5pとhsa-miR-4276)の組み合わせ
(1)配列番号85と24(マーカー:hsa-miR-6729-5pとhsa-miR-6887-5p)の組み合わせ
(2)配列番号87と24(マーカー:hsa-miR-638とhsa-miR-6887-5p)の組み合わせ
(3)配列番号89と24(マーカー:hsa-miR-3178とhsa-miR-6887-5p)の組み合わせ
(4)配列番号90と24(マーカー:hsa-miR-3196とhsa-miR-6887-5p)の組み合わせ
(5)配列番号102と24(マーカー:hsa-miR-4508とhsa-miR-6887-5p)の組み合わせ
(1)配列番号85と10(マーカー:hsa-miR-6729-5pとhsa-miR-6795-5p)の組み合わせ
(2)配列番号87と10(マーカー:hsa-miR-638とhsa-miR-6795-5p)の組み合わせ
(3)配列番号90と10(マーカー:hsa-miR-3196とhsa-miR-6795-5p)の組み合わせ
(4)配列番号88と10(マーカー:hsa-miR-6125とhsa-miR-6795-5p)の組み合わせ
(5)配列番号2と10(マーカー:hsa-miR-1181とhsa-miR-6795-5p)の組み合わせ
(1)配列番号85と52(マーカー:hsa-miR-6729-5pとhsa-miR-4688)の組み合わせ
(2)配列番号88と52(マーカー:hsa-miR-6125とhsa-miR-4688)の組み合わせ
(3)配列番号87と52(マーカー:hsa-miR-638とhsa-miR-4688)の組み合わせ
(4)配列番号98と52(マーカー:hsa-miR-6724-5pとhsa-miR-4688)の組み合わせ
(5)配列番号84と52(マーカー:hsa-miR-1908-5pとhsa-miR-4688)の組み合わせ
(1)配列番号87と9(マーカー:hsa-miR-638とhsa-miR-4675)の組み合わせ
(2)配列番号89と9(マーカー:hsa-miR-3178とhsa-miR-4675)の組み合わせ
(3)配列番号85と9(マーカー:hsa-miR-6729-5pとhsa-miR-4675)の組み合わせ
(4)配列番号117と9(マーカー:hsa-miR-4787-5pとhsa-miR-4675)の組み合わせ
(5)配列番号88と9(マーカー:hsa-miR-6125とhsa-miR-4675)の組み合わせ
(1)配列番号87と11(マーカー:hsa-miR-638とhsa-miR-4731-5p)の組み合わせ
(2)配列番号85と11(マーカー:hsa-miR-6729-5pとhsa-miR-4731-5p)の組み合わせ
(3)配列番号89と11(マーカー:hsa-miR-3178とhsa-miR-4731-5p)の組み合わせ
(4)配列番号102と11(マーカー:hsa-miR-4508とhsa-miR-4731-5p)の組み合わせ
(5)配列番号84と11(マーカー:hsa-miR-1908-5pとhsa-miR-4731-5p)の組み合わせ
(1)配列番号85と19(マーカー:hsa-miR-6729-5pとhsa-miR-4728-5p)の組み合わせ
(2)配列番号87と19(マーカー:hsa-miR-638とhsa-miR-4728-5p)の組み合わせ
(3)配列番号88と19(マーカー:hsa-miR-6125とhsa-miR-4728-5p)の組み合わせ
(4)配列番号89と19(マーカー:hsa-miR-3178とhsa-miR-4728-5p)の組み合わせ
(5)配列番号106と19(マーカー:hsa-miR-4695-5pとhsa-miR-4728-5p)の組み合わせ
(1)配列番号87と39(マーカー:hsa-miR-638とhsa-miR-6861-5p)の組み合わせ
(2)配列番号85と39(マーカー:hsa-miR-6729-5pとhsa-miR-6861-5p)の組み合わせ
(3)配列番号88と39(マーカー:hsa-miR-6125とhsa-miR-6861-5p)の組み合わせ
(4)配列番号84と39(マーカー:hsa-miR-1908-5pとhsa-miR-6861-5p)の組み合わせ
(5)配列番号2と39(マーカー:hsa-miR-1181とhsa-miR-6861-5p)の組み合わせ
(1)配列番号87と61(マーカー:hsa-miR-638とhsa-miR-498)の組み合わせ
(2)配列番号85と61(マーカー:hsa-miR-6729-5pとhsa-miR-498)の組み合わせ
(3)配列番号88と61(マーカー:hsa-miR-6125とhsa-miR-498)の組み合わせ
(4)配列番号108と61(マーカー:hsa-miR-3197とhsa-miR-498)の組み合わせ
(5)配列番号93と61(マーカー:hsa-miR-4746-3pとhsa-miR-498)の組み合わせ
(1)配列番号88と7(マーカー:hsa-miR-6125とhsa-miR-149-3p)の組み合わせ
(2)配列番号85と7(マーカー:hsa-miR-6729-5pとhsa-miR-149-3p)の組み合わせ
(3)配列番号87と7(マーカー:hsa-miR-638とhsa-miR-149-3p)の組み合わせ
(4)配列番号86と7(マーカー:hsa-miR-5195-3pとhsa-miR-149-3p)の組み合わせ
(5)配列番号91と7(マーカー:hsa-miR-8069とhsa-miR-149-3p)の組み合わせ
(1)配列番号85と17(マーカー:hsa-miR-6729-5pとhsa-miR-6738-5p)の組み合わせ
(2)配列番号87と17(マーカー:hsa-miR-638とhsa-miR-6738-5p)の組み合わせ
(3)配列番号89と17(マーカー:hsa-miR-3178とhsa-miR-6738-5p)の組み合わせ
(4)配列番号102と17(マーカー:hsa-miR-4508とhsa-miR-6738-5p)の組み合わせ
(5)配列番号84と17(マーカー:hsa-miR-1908-5pとhsa-miR-6738-5p)の組み合わせ
(1)配列番号85と22(マーカー:hsa-miR-6729-5pとhsa-miR-6785-5p)の組み合わせ
(2)配列番号87と22(マーカー:hsa-miR-638とhsa-miR-6785-5p)の組み合わせ
(3)配列番号102と22(マーカー:hsa-miR-4508とhsa-miR-6785-5p)の組み合わせ
(4)配列番号89と22(マーカー:hsa-miR-3178とhsa-miR-6785-5p)の組み合わせ
(5)配列番号117と22(マーカー:hsa-miR-4787-5pとhsa-miR-6785-5p)の組み合わせ
(1)配列番号85と26(マーカー:hsa-miR-6729-5pとhsa-miR-1228-5p)の組み合わせ
(2)配列番号87と26(マーカー:hsa-miR-638とhsa-miR-1228-5p)の組み合わせ
(3)配列番号88と26(マーカー:hsa-miR-6125とhsa-miR-1228-5p)の組み合わせ
(4)配列番号84と26(マーカー:hsa-miR-1908-5pとhsa-miR-1228-5p)の組み合わせ
(5)配列番号94と26(マーカー:hsa-miR-4689とhsa-miR-1228-5p)の組み合わせ
(1)配列番号85と74(マーカー:hsa-miR-6729-5pとhsa-miR-4690-5p)の組み合わせ
(2)配列番号2と74(マーカー:hsa-miR-1181とhsa-miR-4690-5p)の組み合わせ
(3)配列番号87と74(マーカー:hsa-miR-638とhsa-miR-4690-5p)の組み合わせ
(4)配列番号84と74(マーカー:hsa-miR-1908-5pとhsa-miR-4690-5p)の組み合わせ
(5)配列番号88と74(マーカー:hsa-miR-6125とhsa-miR-4690-5p)の組み合わせ
(1)配列番号90と21(マーカー:hsa-miR-3196とhsa-miR-4257)の組み合わせ
(2)配列番号2と21(マーカー:hsa-miR-1181とhsa-miR-4257)の組み合わせ
(3)配列番号106と21(マーカー:hsa-miR-4695-5pとhsa-miR-4257)の組み合わせ
(4)配列番号84と21(マーカー:hsa-miR-1908-5pとhsa-miR-4257)の組み合わせ
(5)配列番号85と21(マーカー:hsa-miR-6729-5pとhsa-miR-4257)の組み合わせ
(1)配列番号85と28(マーカー:hsa-miR-6729-5pとhsa-miR-6782-5p)の組み合わせ
(2)配列番号84と28(マーカー:hsa-miR-1908-5pとhsa-miR-6782-5p)の組み合わせ
(3)配列番号86と28(マーカー:hsa-miR-5195-3pとhsa-miR-6782-5p)の組み合わせ
(4)配列番号87と28(マーカー:hsa-miR-638とhsa-miR-6782-5p)の組み合わせ
(5)配列番号93と28(マーカー:hsa-miR-4746-3pとhsa-miR-6782-5p)の組み合わせ
(1)配列番号12と137と119と105と237(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-373-5p)の組み合わせ
(2)配列番号87と12と137と119と105(マーカー:hsa-miR-638とhsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(3)配列番号12と103と137と105と247(マーカー:hsa-miR-5090とhsa-miR-6085とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(4)配列番号12と137と119と92と105(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-4723-5pとhsa-miR-642a-3p)の組み合わせ
(5)配列番号12と137と119と105と121(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-602)の組み合わせ
(6)配列番号12と137と1と119と105(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6784-5pとhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(7)配列番号12と137と119と124と105(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-5100とhsa-miR-642a-3p)の組み合わせ
(8)配列番号12と137と119と105と32(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6087)の組み合わせ
(9)配列番号12と137と119と105と100(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6875-5p)の組み合わせ
(10)配列番号12と137と119と105と86(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-5195-3p)の組み合わせ
(11)配列番号12と137と119と105と153(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-296-5p)の組み合わせ
(12)配列番号12と137と119と105と141(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-663a)の組み合わせ
(13)配列番号12と137と105と246と153(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6766-3pとhsa-miR-296-5p)の組み合わせ
(14)配列番号12と97と137と105と153(マーカー:hsa-miR-5090とhsa-miR-7109-5pとhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-296-5p)の組み合わせ
(15)配列番号12と103と137と119と105(マーカー:hsa-miR-5090とhsa-miR-6085とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(16)配列番号12と137と119と105と246(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6766-3p)の組み合わせ
(17)配列番号12と137と92と105と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-4723-5pとhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(18)配列番号12と137と124と105と153(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-5100とhsa-miR-642a-3pとhsa-miR-296-5p)の組み合わせ
(19)配列番号12と137と105と32と153(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6087とhsa-miR-296-5p)の組み合わせ
(20)配列番号12と137と105と13と121(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-3620-5pとhsa-miR-602)の組み合わせ
(21)配列番号106と12と137と119と105(マーカー:hsa-miR-4695-5pとhsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(22)配列番号12と137と119と105と13(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-3620-5p)の組み合わせ
(23)配列番号12と137と119と105と140(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-4640-5p)の組み合わせ
(24)配列番号12と137と119と105と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(25)配列番号12と137と119と105と109(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6769b-5p)の組み合わせ
(26)配列番号12と137と105と109と121(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6769b-5pとhsa-miR-602)の組み合わせ
(27)配列番号12と103と137と105と121(マーカー:hsa-miR-5090とhsa-miR-6085とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-602)の組み合わせ
(28)配列番号12と137と105と32と121(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6087とhsa-miR-602)の組み合わせ
(29)配列番号12と137と124と105と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-5100とhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(30)配列番号12と137と105と246と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6766-3pとhsa-miR-4286)の組み合わせ
(31)配列番号12と137と105と153と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-296-5pとhsa-miR-4286)の組み合わせ
(32)配列番号12と137と105と247と141(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4286とhsa-miR-663a)の組み合わせ
(33)配列番号12と137と105と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(34)配列番号12と137と105と140と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4640-5pとhsa-miR-4286)の組み合わせ
(35)配列番号12と119と124と105と140(マーカー:hsa-miR-5090とhsa-miR-6813-5pとhsa-miR-5100とhsa-miR-642a-3pとhsa-miR-4640-5p)の組み合わせ
(36)配列番号12と119と105と100と140(マーカー:hsa-miR-5090とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6875-5pとhsa-miR-4640-5p)の組み合わせ
(37)配列番号90と12と119と105と140(マーカー:hsa-miR-3196とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-4640-5p)の組み合わせ
(38)配列番号90と12と137と119と105(マーカー:hsa-miR-3196とhsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(39)配列番号90と12と137と105と32(マーカー:hsa-miR-3196とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6087)の組み合わせ
(40)配列番号90と12と137と105と153(マーカー:hsa-miR-3196とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-296-5p)の組み合わせ
(41)配列番号90と12と119と105と100(マーカー:hsa-miR-3196とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6875-5p)の組み合わせ
(42)配列番号90と12と119と109と140(マーカー:hsa-miR-3196とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-6769b-5pとhsa-miR-4640-5p)の組み合わせ
(43)配列番号87と12と137と105と247(マーカー:hsa-miR-638とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(44)配列番号90と12と109と140と237(マーカー:hsa-miR-3196とhsa-miR-5090とhsa-miR-6769b-5pとhsa-miR-4640-5pとhsa-miR-373-5p)の組み合わせ
(45)配列番号12と137と105と109と153(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6769b-5pとhsa-miR-296-5p)の組み合わせ
(46)配列番号12と137と105と109と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6769b-5pとhsa-miR-4286)の組み合わせ
(47)配列番号12と137と109と140と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6769b-5pとhsa-miR-4640-5pとhsa-miR-4286)の組み合わせ
(48)配列番号12と137と109と121と237(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6769b-5pとhsa-miR-602とhsa-miR-373-5p)の組み合わせ
(49)配列番号12と137と119と105と175(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6768-5p)の組み合わせ
(50)配列番号12と137と109と175と121(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6769b-5pとhsa-miR-6768-5pとhsa-miR-602)の組み合わせ
(51)配列番号87と12と119と105と175(マーカー:hsa-miR-638とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6768-5p)の組み合わせ
(52)配列番号12と137と119と105と111(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-187-5p)の組み合わせ
(53)配列番号12と137と119と105と24(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6887-5p)の組み合わせ
(54)配列番号12と137と105と32と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6087とhsa-miR-4286)の組み合わせ
(55)配列番号90と12と137と105と237(マーカー:hsa-miR-3196とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-373-5p)の組み合わせ
(56)配列番号12と84と137と119と105(マーカー:hsa-miR-5090とhsa-miR-1908-5pとhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(57)配列番号12と97と137と105と247(マーカー:hsa-miR-5090とhsa-miR-7109-5pとhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(58)配列番号87と12と137と105と237(マーカー:hsa-miR-638とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-373-5p)の組み合わせ
(59)配列番号87と12と100と109と237(マーカー:hsa-miR-638とhsa-miR-5090とhsa-miR-6875-5pとhsa-miR-6769b-5pとhsa-miR-373-5p)の組み合わせ
(60)配列番号87と12と100と109と237(マーカー:hsa-miR-638とhsa-miR-5090とhsa-miR-6875-5pとhsa-miR-6769b-5pとhsa-miR-373-5p)の組み合わせ
(61)配列番号106と12と137と105と86(マーカー:hsa-miR-4695-5pとhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-5195-3p)の組み合わせ
(62)配列番号106と12と137と105と247(マーカー:hsa-miR-4695-5pとhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(63)配列番号106と12と119と105と100(マーカー:hsa-miR-4695-5pとhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6875-5p)の組み合わせ
(64)配列番号106と12と137と105と121(マーカー:hsa-miR-4695-5pとhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-602)の組み合わせ
(1)配列番号137と119と105と28と237(マーカー:hsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6782-5pとhsa-miR-373-5p)の組み合わせ
(2)配列番号87と106と119と28と121(マーカー:hsa-miR-638とhsa-miR-4695-5pとhsa-miR-6813-5pとhsa-miR-6782-5pとhsa-miR-602)の組み合わせ
(3)配列番号106と137と119と28と121(マーカー:hsa-miR-4695-5pとhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-6782-5pとhsa-miR-602)の組み合わせ
(4)配列番号90と119と105と28と237(マーカー:hsa-miR-3196とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6782-5pとhsa-miR-373-5p)の組み合わせ
(1)配列番号90と5と137と119と105(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(2)配列番号5と137と119と105と237(マーカー:hsa-miR-4276とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-373-5p)の組み合わせ
(3)配列番号5と137と119と105と32(マーカー:hsa-miR-4276とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6087)の組み合わせ
(1)配列番号2と137と119と105と237(マーカー:hsa-miR-1181とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-373-5p)の組み合わせ
(2)配列番号2と87と137と119と105(マーカー:hsa-miR-1181とhsa-miR-638とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(3)配列番号2と137と119と105と13(マーカー:hsa-miR-1181とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-3620-5p)の組み合わせ
(4)配列番号2と137と119と105と121(マーカー:hsa-miR-1181とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-602)の組み合わせ
(5)配列番号2と137と119と105と247(マーカー:hsa-miR-1181とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(6)配列番号2と87と119と109と247(マーカー:hsa-miR-1181とhsa-miR-638とhsa-miR-6813-5pとhsa-miR-6769b-5pとhsa-miR-4286)の組み合わせ
(7)配列番号2と90と137と119と105(マーカー:hsa-miR-1181とhsa-miR-3196とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(8)配列番号2と137と119と105と140(マーカー:hsa-miR-1181とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-4640-5p)の組み合わせ
(9)配列番号2と87と119と105と237(マーカー:hsa-miR-1181とhsa-miR-638とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-373-5p)の組み合わせ
(1)配列番号12と137と105と28と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6782-5pとhsa-miR-4286)の組み合わせ
(2)配列番号12と137と119と105と28(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-6782-5p)の組み合わせ
(3)配列番号12と103と137と105と28(マーカー:hsa-miR-5090とhsa-miR-6085とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-6782-5p)の組み合わせ
(4)配列番号12と84と28と140と121(マーカー:hsa-miR-5090とhsa-miR-1908-5pとhsa-miR-6782-5pとhsa-miR-4640-5pとhsa-miR-602)の組み合わせ
(5)配列番号12と137と28と109と121(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6782-5pとhsa-miR-6769b-5pとhsa-miR-602)の組み合わせ
(6)配列番号12と1と28と121と247(マーカー:hsa-miR-5090とhsa-miR-6784-5pとhsa-miR-6782-5pとhsa-miR-602とhsa-miR-4286)の組み合わせ
(7)配列番号12と119と28と100と121(マーカー:hsa-miR-5090とhsa-miR-6813-5pとhsa-miR-6782-5pとhsa-miR-6875-5pとhsa-miR-602)の組み合わせ
(8)配列番号12と92と28と100と247(マーカー:hsa-miR-5090とhsa-miR-4723-5pとhsa-miR-6782-5pとhsa-miR-6875-5pとhsa-miR-4286)の組み合わせ
(9)配列番号12と28と100と140と247(マーカー:hsa-miR-5090とhsa-miR-6782-5pとhsa-miR-6875-5pとhsa-miR-4640-5pとhsa-miR-4286)の組み合わせ
(10)配列番号12と137と28と109と247(マーカー:hsa-miR-5090とhsa-miR-4673とhsa-miR-6782-5pとhsa-miR-6769b-5pとhsa-miR-4286)の組み合わせ
(11)配列番号12と84と28と109と121(マーカー:hsa-miR-5090とhsa-miR-1908-5pとhsa-miR-6782-5pとhsa-miR-6769b-5pとhsa-miR-602)の組み合わせ
(12)配列番号12と103と1と28と121(マーカー:hsa-miR-5090とhsa-miR-6085とhsa-miR-6784-5pとhsa-miR-6782-5pとhsa-miR-602)の組み合わせ
(13)配列番号12と1と28と32と121(マーカー:hsa-miR-5090とhsa-miR-6784-5pとhsa-miR-6782-5pとhsa-miR-6087とhsa-miR-602)の組み合わせ
(14)配列番号12と1と28と100と121(マーカー:hsa-miR-5090とhsa-miR-6784-5pとhsa-miR-6782-5pとhsa-miR-6875-5pとhsa-miR-602)の組み合わせ
(15)配列番号12と1と28と175と121(マーカー:hsa-miR-5090とhsa-miR-6784-5pとhsa-miR-6782-5pとhsa-miR-6768-5pとhsa-miR-602)の組み合わせ
(1)配列番号5と12と137と119と105(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(2)配列番号90と5と12と119と105(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(3)配列番号5と12と137と105と121(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-602)の組み合わせ
(4)配列番号5と12と119と92と121(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-4723-5pとhsa-miR-602)の組み合わせ
(5)配列番号90と5と12と109と247(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-5090とhsa-miR-6769b-5pとhsa-miR-4286)の組み合わせ
(6)配列番号5と12と137と109と121(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-4673とhsa-miR-6769b-5pとhsa-miR-602)の組み合わせ
(7)配列番号5と12と137と109と247(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-4673とhsa-miR-6769b-5pとhsa-miR-4286)の組み合わせ
(8)配列番号90と5と106と12と109(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-4695-5pとhsa-miR-5090とhsa-miR-6769b-5p)の組み合わせ
(9)配列番号90と5と12と137と105(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3p)の組み合わせ
(10)配列番号90と5と12と119と109(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-6769b-5p)の組み合わせ
(11)配列番号90と5と12と105と109(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-5090とhsa-miR-642a-3pとhsa-miR-6769b-5p)の組み合わせ
(12)配列番号5と12と137と105と153(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-296-5p)の組み合わせ
(13)配列番号5と12と119と105と54(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-642a-3pとhsa-miR-5787)の組み合わせ
(14)配列番号87と5と106と12と109(マーカー:hsa-miR-638とhsa-miR-4276とhsa-miR-4695-5pとhsa-miR-5090とhsa-miR-6769b-5p)の組み合わせ
(15)配列番号87と5と12と137と105(マーカー:hsa-miR-638とhsa-miR-4276とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3p)の組み合わせ
(16)配列番号90と5と12と1と105(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-5090とhsa-miR-6784-5pとhsa-miR-642a-3p)の組み合わせ
(17)配列番号90と5と12と109と86(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-5090とhsa-miR-6769b-5pとhsa-miR-5195-3p)の組み合わせ
(18)配列番号5と12と137と105と247(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(19)配列番号90と5と12と109と175(マーカー:hsa-miR-3196とhsa-miR-4276とhsa-miR-5090とhsa-miR-6769b-5pとhsa-miR-6768-5p)の組み合わせ
(20)配列番号5と12と100と109と121(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-6875-5pとhsa-miR-6769b-5pとhsa-miR-602)の組み合わせ
(1)配列番号2と12と137と119と105(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-4673とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(2)配列番号2と12と137と105と153(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-296-5p)の組み合わせ
(3)配列番号2と12と137と105と121(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-602)の組み合わせ
(4)配列番号2と12と109と121と247(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-6769b-5pとhsa-miR-602とhsa-miR-4286)の組み合わせ
(5)配列番号2と90と12と119と105(マーカー:hsa-miR-1181とhsa-miR-3196とhsa-miR-5090とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(6)配列番号2と90と12と109と140(マーカー:hsa-miR-1181とhsa-miR-3196とhsa-miR-5090とhsa-miR-6769b-5pとhsa-miR-4640-5p)の組み合わせ
(7)配列番号2と12と100と109と121(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-6875-5pとhsa-miR-6769b-5pとhsa-miR-602)の組み合わせ
(8)配列番号2と12と109と175と121(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-6769b-5pとhsa-miR-6768-5pとhsa-miR-602)の組み合わせ
(9)配列番号2と12と97と105と247(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-7109-5pとhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(10)配列番号2と12と137と105と247(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-4673とhsa-miR-642a-3pとhsa-miR-4286)の組み合わせ
(11)配列番号2と12と137と109と121(マーカー:hsa-miR-1181とhsa-miR-5090とhsa-miR-4673とhsa-miR-6769b-5pとhsa-miR-602)の組み合わせ
(1)配列番号2と90と5と119と105(マーカー:hsa-miR-1181とhsa-miR-3196とhsa-miR-4276とhsa-miR-6813-5pとhsa-miR-642a-3p)の組み合わせ
(2)配列番号2と5と119と109と121(マーカー:hsa-miR-1181とhsa-miR-4276とhsa-miR-6813-5pとhsa-miR-6769b-5pとhsa-miR-602)の組み合わせ
(3)配列番号2と5と119と86と121(マーカー:hsa-miR-1181とhsa-miR-4276とhsa-miR-6813-5pとhsa-miR-5195-3pとhsa-miR-602)の組み合わせ
(1)配列番号5と12と1と28と121(マーカー:hsa-miR-4276とhsa-miR-5090とhsa-miR-6784-5pとhsa-miR-6782-5pとhsa-miR-602)の組み合わせ
本発明はさらに、上記3.で説明した本発明のキット又はデバイス(本発明で使用可能な上記の核酸を含む。)を用いて、血液、血清、血漿等の検体中の、以下の群から選択される、miR-6784-5p、miR-1181、miR-671-5p、miR-6857-5p、miR-4276、miR-1914-3p、miR-149-3p、miR-937-5p、miR-4675、miR-6795-5p、miR-4731-5p、miR-5090、miR-3620-5p、miR-1343-5p、miR-6717-5p、miR-6825-5p、miR-6738-5p、miR-6769a-5p、miR-4728-5p、miR-652-5p、miR-4257、miR-6785-5p、miR-7110-5p、miR-6887-5p、miR-887-3p、miR-1228-5p、miR-5572、miR-6782-5p、miR-4298、miR-6786-5p、miR-5010-5p、miR-6087、miR-6765-5p、miR-6732-5p、miR-6787-5p、miR-6737-5p、miR-128-2-5p、miR-4270、miR-6861-5p、miR-6756-5p、miR-1229-5p、miR-6891-5p、miR-6848-5p、miR-1237-5p、miR-30c-1-3p、miR-1233-5p、miR-211-3p、miR-4758-5p、miR-614、miR-6746-5p、miR-1915-5p、miR-4688、miR-3917、miR-5787、miR-4632-5p、miR-6126、miR-135a-3p、miR-8063、miR-5698、miR-6089、miR-498、miR-296-3p、miR-4419b、miR-6802-5p、miR-6829-5p、miR-6803-5p、miR-1199-5p、miR-6840-3p、miR-6752-5p、miR-6798-5p、miR-6131、miR-4667-5p、miR-6510-5p、miR-4690-5p、miR-920、miR-23b-3p、miR-4448、miR-2110、miR-4706、miR-7845-5p、miR-6808-5p、miR-4447、miR-6869-5p、miR-6794-5p、miR-6511a-5p、miR-6824-5p、miR-6766-3p、miR-6511a-5p、及び、miR-6749-5pで表される少なくとも1つの早期膵がん又は膵がん前駆病変由来の遺伝子の発現量、並びに場合により、以下の群から選択される、miR-1908-5p、miR-6729-5p、miR-5195-3p、miR-638、miR-6125、miR-3178、miR-3196、miR-8069、miR-4723-5p、miR-4746-3p、miR-4689、miR-6816-5p、miR-6757-5p、miR-7109-5p、miR-6724-5p、miR-1225-3p、miR-6875-5p、miR-7108-5p、miR-4508、miR-6085、miR-6779-5p、miR-642a-3p、miR-4695-5p、miR-7847-3p、miR-3197、miR-6769b-5p、miR-7641、miR-187-5p、miR-3185、miR-2861、miR-3940-5p、miR-1203、miR-615-5p、miR-4787-5p、miR-1343-3p、miR-6813-5p、miR-1225-5p、miR-602、miR-4488、miR-125a-3p、miR-5100、miR-4294、miR-1231、miR-6765-3p、miR-4442、miR-718、miR-6780b-5p、miR-6090、miR-6845-5p、miR-4741、miR-4467、miR-4707-5p、miR-4271、miR-4673、miR-3184-5p、miR-1469、miR-4640-5p、miR-663a、miR-6791-5p、miR-6826-5p、miR-4433b-3p、miR-1915-3p、miR-4417、miR-4449、miR-4707-3p、miR-3180-3p、miR-5585-3p、miR-1268a、miR-8072、miR-296-5p、miR-204-3p、miR-4454、miR-6722-3p、miR-1290、miR-3622a-5p、miR-939-5p、miR-675-5p、miR-3131、miR-4648、miR-1268b、miR-6741-5p、miR-6893-5p、miR-3162-5p、miR-642b-3p、miR-4734、miR-150-3p、miR-8089、miR-6805-3p、miR-7113-3p、miR-6850-5p、miR-6799-5p、miR-6768-5p、miR-92b-5p、miR-3679-5p、miR-4792、miR-3656、miR-92a-2-5p、miR-4466、miR-4513、miR-6781-5p、miR-4649-5p、miR-6775-5p、miR-4651、miR-3195、miR-6726-5p、miR-6872-3p、miR-371a-5p、miR-6777-5p、miR-6789-5p、miR-7975、miR-6821-5p、miR-4534、miR-619-5p、miR-7107-5p、miR-1228-3p、miR-6774-5p、miR-6805-5p、miR-23a-3p、miR-4665-5p、miR-4505、miR-4638-5p、miR-24-3p、miR-3135b、miR-4745-5p、miR-128-1-5p、miR-4476、miR-4687-3p、miR-3665、miR-6806-5p、miR-3937、miR-711、miR-3141、miR-3188、miR-4281、miR-5196-5p、miR-6880-5p、miR-3960、miR-3648、miR-6721-5p、miR-4492、miR-744-5p、miR-7704、miR-4749-5p、miR-762、miR-6836-3p、miR-6727-5p、miR-4739、miR-7977、miR-4484、miR-6515-3p、miR-373-5p、miR-4258、miR-4674、miR-3180、miR-6076、miR-1238-5p、miR-4463、miR-4486、miR-4730、miR-4286、及び、miR-4739で表される少なくとも1つの早期膵がん又は膵がん前駆病変由来の遺伝子の発現量をin vitroで測定する。そのようにして測定された発現量と、同様に測定された健常体(非膵がん及び非膵がん前駆病変患者を含む)の対照発現量とを用いて、たとえば統計学的に有意に差がある両発現量を比較して、或いは、検体中の上記遺伝子の発現量と判別式(下記参照)から決定された判別得点によって、被験体が早期膵がん又は膵がん前駆病変に罹患しているかどうかをin vitroで評価し、それによって被験体における早期膵がん又は膵がん前駆病変の存在又は不存在を検出することを含む、被験体における早期膵がん又は膵がん前駆病変の検出方法を提供する。
(a)被験体由来の検体を、in vitroで、本発明のキット又はデバイス中のポリヌクレオチドと接触させるステップ、
(b)検体中の標的核酸の発現量を、上記ポリヌクレオチドを核酸プローブ又はプライマーとして用いて測定するステップ、
(c)(b)の結果をもとに、被験体が早期膵がん又は膵がん前駆病変(細胞)に罹患しているかどうかを評価し、それによって被験体における早期膵がん又は膵がん前駆病変(細胞)の存在又は不存在を検出するステップ、
を含むことができる。
(a)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(b)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列を含むポリヌクレオチド、
(c)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(d)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、に相補的な塩基配列を含むポリヌクレオチド、及び
(e)前記(a)~(d)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択される。
(f)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(g)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列を含むポリヌクレオチド、
(h)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(i)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列、もしくは当該塩基配列においてuがtである塩基配列、に相補的な塩基配列を含むポリヌクレオチド、及び
(j)前記(f)~(i)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、からなる群から選択されるポリヌクレオチドである。
(a)被験体の検体から調製されたRNA又はそれから転写された相補的ポリヌクレオチド(cDNA)を、本発明のキット又はデバイス中のポリヌクレオチドと結合させるステップ、
(b)当該ポリヌクレオチドに結合した検体由来のRNA又は当該RNAから合成されたcDNAを、上記ポリヌクレオチドを核酸プローブとして用いるハイブリダイゼーションによって、あるいは、ポリヌクレオチドの塩基配列を特定するシーケンサーによって、あるいは、上記ポリヌクレオチドをプライマーとして用いる定量RT-PCRによって、定量的に又は定性的に測定するステップ、
(c)上記(b)の測定結果に基づいて、対照と比較して被験体が早期膵がん又は膵がん前駆病変に罹患していること、又は早期膵がん又は膵がん前駆病変に罹患していないことをin vitroで評価し、それによって被験体における早期膵がん又は膵がん前駆病変(由来の遺伝子の発現)の存在又は不存在を検出するステップ、
を含むことができる。
(a)早期膵がん又は膵がん前駆病変患者由来であること及び健常体又は早期膵がん又は膵がん前駆病変を含まない被験体由来であることが既に知られている検体中の標的遺伝子の発現量を、本発明による検出用ポリヌクレオチド、キット又はデバイス(例えばDNAチップ)を用いて測定するステップ、
(b)(a)で測定された発現量の測定値から、上記の式1~3、5及び6の判別式を作成するステップ、
(c)被験体由来の検体中の当該標的遺伝子の発現量を、本発明による診断(検出)用ポリヌクレオチド、キット又はデバイス(例えばDNAチップ)を用いて測定し、(b)で作成した判別式にそれらを代入して、得られた結果に基づいて被験体が早期膵がん又は膵がん前駆病変を含むこと又は含まないことを決定又は評価する、或いは早期膵がん又は膵がん前駆病変由来の発現量を健常体由来の対照と比較し評価する、ステップ、
を含むことができる。
<早期膵がん又は膵がん前駆病変患者と健常体の検体の採取>
インフォームドコンセントを得た、臓器にがんが認められていない膵がん前駆病変患者21人(IPMA low gradeが4例、IPMA high gradeが5例、IPMCが12例)、膵臓以外の臓器にがんが認められていない早期膵がん患者31人(stage IIAが9例、stage IIBが22例)、及び、健常体123人からベノジェクトII真空採血管VP-AS109K60(テルモ株式会社、日本国)を用いてそれぞれ血清を採取し、学習検体群とした。同様に、インフォームドコンセントを得た、臓器にがんが認められていない膵がん前駆病変患者12人(IPMA low gradeが3例、IPMA high gradeが3例、IPMCが6例)、膵臓以外の臓器にがんが認められていない早期膵がん患者13人(stage IIAが3例、stage IIBが10例)、及び、健常体61人からベノジェクトII真空採血管VP-AS109K60(テルモ株式会社)を用いてそれぞれ血清を採取し、検証検体群とした。
検体として上記学習検体群、検証検体群合わせて膵がん前駆病変患者33人、健常体184人、及び、早期膵がん患者44人の合計261人からそれぞれ得られた血清300μLから、3D-Gene(登録商標)RNA extraction reagent from liquid sample kit(東レ株式会社、日本国)中のRNA抽出用試薬を用いて、同社の定めるプロトコールに従ってtotal RNAを得た。
検体として上記学習検体群、検証検体群合わせて膵がん前駆病変患者33人、健常体184人、及び、早期膵がん患者44人の合計261人の血清から得たtotal RNAに対して、3D-Gene(登録商標) miRNA Labeling kit(東レ株式会社)を用いて同社が定めるプロトコール(ver2.20)に基づいてmiRNAを蛍光標識した。オリゴDNAチップとして、miRBase release 20に登録されているmiRNAの中で、2,555種のmiRNAと相補的な配列を有するプローブを搭載した3D-Gene(登録商標) Human miRNA Oligo chip(東レ株式会社)を用い、同社が定めるプロトコールに基づいてストリンジェントな条件でハイブリダイゼーション及びハイブリダイゼーション後の洗浄を行った。DNAチップを3D-Gene(登録商標)スキャナー(東レ株式会社)を用いてスキャンし、画像を取得して3D-Gene(登録商標)Extraction(東レ株式会社)にて蛍光強度を数値化した。数値化された蛍光強度を、底が2の対数値に変換して遺伝子発現量とし、ブランク値の減算を行い、欠損値は各DNAチップにおける遺伝子発現量の最小値の対数値から0.1を減算した値で置換した。その結果、膵がん前駆病変患者33人、健常体184人、及び、早期膵がん患者46人の合計261人の血清に対する、網羅的なmiRNAの遺伝子発現量を得た。数値化されたmiRNAの遺伝子発現量を用いた計算及び統計解析は、R言語3.0.2(R Development Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing, URL http://www.R-project.org/.)及びMASSパッケージ7.3-30(Venables, W. N. & Ripley, B. D. (2002) Modern Applied Statistics with S. Fourth Edition. Springer, New York. ISBN 0-387-95457-0)を用いて実施した。
<他のがんと良性疾患の検体の採取>
インフォームドコンセントを得た他の臓器にがんが認められていない、進行膵がん患者61人、胆道がん患者66人、大腸がん患者31人、胃がん患者32人、食道がん患者34人、肝がん患者38人、及び、膵臓良性疾患患者15人からベノジェクトII真空採血管VP-AS109K60(テルモ株式会社)を用いてそれぞれ血清を採取し、また、遺伝子発現情報データベースであるGene Expression Omnibus(http://www.ncbi.nlm.nih.gov/geo/)のアクセッション番号:GSE73002のデータセットから、乳がん患者51人、前立腺がん患者35人、前立腺良性疾患患者26人のデータを抽出し、参考例1の膵がん前駆病変患者21人(IPMA low gradeが4例、IPMA high gradeが5例、IPMCが12例)、早期膵がん患者31人(stage IIAが8例、stage IIBが22例)、及び、健常体128人と合わせて学習検体群とした。同様に、インフォームドコンセントを得た他の臓器にがんが認められていない進行膵がん患者39人、胆道がん患者32人、大腸がん患者19人、胃がん患者18人、食道がん患者16人、肝がん患者14人、及び、膵臓良性疾患患者9人からベノジェクトII真空採血管VP-AS109K60(テルモ株式会社)を用いてそれぞれ血清を採取し、また、遺伝子発現情報データベースであるGene Expression Omnibus(http://www.ncbi.nlm.nih.gov/geo/)のアクセッション番号:GSE73002のデータセットから、乳がん患者23人、前立腺がん患者17人、前立腺良性疾患患者15人のデータを抽出し、参考例1の膵がん前駆病変患者12人(IPMA low gradeが3例、IPMA high gradeが3例、IPMCが6例)、早期膵がん患者13人(stage IIAが3例、stage IIBが10例)、及び、健常体56人と合わせて検証検体群とした。以降のtotal RNAの抽出並びに遺伝子発現量の測定及び解析は参考例1と同様に行った。
<学習検体群の検体を用いた遺伝子マーカーの選定と検証検体群の検体を用いた単独の遺伝子マーカーの早期膵がん又は膵がん前駆病変判別性能の評価方法>
本実施例では、学習検体群から早期膵がん又は膵がん前駆病変を陽性対照群、健常体を陰性対照群として判別するための遺伝子マーカーを選定し、学習検体群とは独立した検証検体群の検体において検討した。
<検証検体群検体を用いた複数の遺伝子マーカーの組合せによる早期膵がん又は膵がん前駆病変判別性能の評価方法A>
本実施例では、実施例1で選定された遺伝子マーカーを組合せて早期膵がん又は膵がん前駆病変判別性能を評価する方法を検討した。
<全検体を用いた場合の遺伝子マーカーの選定と獲られた遺伝子マーカーの早期膵がん又は膵がん前駆病変判別性能の評価方法>
本実施例では、上記実施例1及び2で用いた学習検体群及び検証検体群の検体を統合し全検体を用いて、遺伝子マーカーの選定及びその早期膵がん又は膵がん前駆病変判別性能評価を行った。
<検証検体群検体を用いた複数の遺伝子マーカーの組合せによる早期膵がん又は膵がん前駆病変特異的な判別性能の評価方法>
本実施例では、参考例2に記載した検体群の学習検体群を対象として、実施例1に記載の方法と同様の方法で、膵がん前駆病変患者群と早期膵がん患者群を陽性対照群として、また、健常体群、進行膵がん患者群、胆道がん患者群、乳がん患者群、前立腺がん患者群、大腸がん患者群、胃がん患者群、食道がん患者群、肝がん患者群、及び、膵臓良性疾患患者群、前立腺良性疾患患者群を陰性対照群として、血清中のmiRNAの遺伝子発現量の比較を行い、追加の診断用遺伝子マーカーを選択した。その結果選択された、追加の診断用遺伝子マーカー(配列番号246~247)と実施例1で選定された遺伝子マーカーとを組合せて早期膵がん又は膵がん前駆病変に特異的な判別性能を評価する方法を検討した。
<検証検体群検体を用いた複数の遺伝子マーカーの組合せによる早期膵がん又は膵がん前駆病変判別性能の評価方法>
実施例2では、実施例1で選定された遺伝子マーカーを複数組み合わせることで、1個の遺伝子マーカーを用いた場合よりも判別性能が向上したことを示した。そこで、本実施例では、実施例1で選定されなかった遺伝子マーカーも実施例1で選定された遺伝子マーカーと組み合わせることで早期膵がん又は膵がん前駆病変を判別する高い性能が得られるか検討した。
<既存血中腫瘍マーカーの早期膵がん又は膵がん前駆病変判別性能>
上記の参考例で得た学習検体群と検証検体群について、既存の腫瘍マーカーCEA及びCA19-9の血中濃度を測定した。これらの腫瘍マーカーは、原則、非特許文献3に記載される基準値(CEAは5ng/mL、CA19-9は37U/mL)よりも血中濃度が高いとがんの疑いがあるとされる。従って、各検体毎にCEA及びCA19-9の血中濃度が基準値を超えているか否かを確認し、早期膵がん又は膵がん前駆病変患者を早期膵がん又は膵がん前駆病変患者として判定しているか見定め、学習検体群及び検証検体群における各既存マーカーの感度を算出した。この結果を表5-1及び表5-2に示した。学習検体群においてはCEAの感度は18%、CA19-9の感度は58%、検証検体群においてはCEAの感度は20%、CA19-9の感度は68%しかなく、いずれのマーカーも早期膵がん又は膵がん前駆病変の検出には有用でないことが分かった(表5-1及び表5-2)。また、学習検体群及び検証検体群において、CEA及びCA19-9は膵がん前駆病変の一種である悪性度の低いIPMA low gradeをまったく検出できなかった(表5-1及び表5-2)。
<既存の血中膵がんmiRNAマーカーの早期膵がん又は膵がん前駆病変に対する性能>
上記の参考例で得た学習検体群と検証検体群について、膵がん患者群をその他のがん患者群から特異的に識別可能であると特許文献2に記載されているhsa-miR-6075、hsa-miR-4294、hsa-miR-6836-3p、hsa-miR-4530、及び、hsa-miR-6880-5pの中で、本発明に含まれるhsa-miR-4294(配列番号125)、hsa-miR-6836-3p(配列番号231)、及び、hsa-miR-6880-5p(配列番号219)から選択される1つ以上のmiRNAの組み合わせについて、早期膵がん又は膵がん前駆病変に対する判別性能を評価した。例えば、配列番号219、125、及び、231で表される塩基配列もしくはその相補的配列からなるポリヌクレオチドの組み合わせは、学習検体群及び検証検体群の両方において精度93%という優れた精度を示したが、学習検体群の感度が50%、特異度が94.7%、検証検体群の感度が72.7%、特異度が93.8%となり、学習検体群と検証検体群の感度に差が生じる傾向がみられる(表11)。
<既存の血中膵がんmiRNAマーカーの早期膵がん又は膵がん前駆病変に対する性能>
特許文献5において健常体群とIPMN患者群の間に統計学的に有意な発現量差があった上位30種のmiRNAの中で、膵がん前駆病変患者群の遺伝子発現量と健常体群の遺伝子発現量のFold Changeが3.0以上であるhsa-miR-145-5p(配列番号813)、hsa-let-7f-5p(配列番号814)、hsa-miR-146a-5p(配列番号815)、hsa-let-7d-5p(配列番号816)、hsa-let-7a-5p(配列番号817)を選択し、上記の参考例で得た学習検体群と検証検体群について、早期膵がん又は膵がん前駆病変に対する判別性能を評価した。配列番号813~817で表される塩基配列もしくはその相補的配列からなるポリヌクレオチドの組み合わせは、学習検体群において感度63.6%、特異度74.5%、検証検体群において感度54.5%、特異度74.7%となった(表12)。
Claims (18)
- 早期膵がん又は膵がん前駆病変マーカーである、miR-6784-5p、miR-1181、miR-671-5p、miR-6857-5p、miR-4276、miR-1914-3p、miR-149-3p、miR-937-5p、miR-4675、miR-6795-5p、miR-4731-5p、miR-5090、miR-3620-5p、miR-1343-5p、miR-6717-5p、miR-6825-5p、miR-6738-5p、miR-6769a-5p、miR-4728-5p、miR-652-5p、miR-4257、miR-6785-5p、miR-7110-5p、miR-6887-5p、miR-887-3p、miR-1228-5p、miR-5572、miR-6782-5p、miR-4298、miR-6786-5p、miR-5010-5p、miR-6087、miR-6765-5p、miR-6732-5p、miR-6787-5p、miR-6737-5p、miR-128-2-5p、miR-4270、miR-6861-5p、miR-6756-5p、miR-1229-5p、miR-6891-5p、miR-6848-5p、miR-1237-5p、miR-30c-1-3p、miR-1233-5p、miR-211-3p、miR-4758-5p、miR-614、miR-6746-5p、miR-1915-5p、miR-4688、miR-3917、miR-5787、miR-4632-5p、miR-6126、miR-135a-3p、miR-8063、miR-5698、miR-6089、miR-498、miR-296-3p、miR-4419b、miR-6802-5p、miR-6829-5p、miR-6803-5p、miR-1199-5p、miR-6840-3p、miR-6752-5p、miR-6798-5p、miR-6131、miR-4667-5p、miR-6510-5p、miR-4690-5p、miR-920、miR-23b-3p、miR-4448、miR-2110、miR-4706、miR-7845-5p、miR-6808-5p、miR-4447、miR-6869-5p、miR-6794-5p、miR-6511a-5p、miR-6824-5p、miR-6766-3p、miR-6511a-5p、及び、miR-6749-5pからなる群から選択される少なくとも1つのポリヌクレオチドと特異的に結合可能な核酸を含む、早期膵がん又は膵がん前駆病変の検出用キット。
- miR-6784-5pがhsa-miR-6784-5pであり、miR-1181がhsa-miR-1181であり、miR-671-5pがhsa-miR-671-5pであり、miR-6857-5pがhsa-miR-6857-5pであり、miR-4276がhsa-miR-4276であり、miR-1914-3pがhsa-miR-1914-3pであり、miR-149-3pがhsa-miR-149-3pであり、miR-937-5pがhsa-miR-937-5pであり、miR-4675がhsa-miR-4675であり、miR-6795-5pがhsa-miR-6795-5pであり、miR-4731-5pがhsa-miR-4731-5pであり、miR-5090がhsa-miR-5090であり、miR-3620-5pがhsa-miR-3620-5pであり、miR-1343-5pがhsa-miR-1343-5pであり、miR-6717-5pがhsa-miR-6717-5pであり、miR-6825-5pがhsa-miR-6825-5pであり、miR-6738-5pがhsa-miR-6738-5pであり、miR-6769a-5pがhsa-miR-6769a-5pであり、miR-4728-5pがhsa-miR-4728-5pであり、miR-652-5pがhsa-miR-652-5pであり、miR-4257がhsa-miR-4257であり、miR-6785-5pがhsa-miR-6785-5pであり、miR-7110-5pがhsa-miR-7110-5pであり、miR-6887-5pがhsa-miR-6887-5pであり、miR-887-3pがhsa-miR-887-3pであり、miR-1228-5pがhsa-miR-1228-5pであり、miR-5572がhsa-miR-5572であり、miR-6782-5pがhsa-miR-6782-5pであり、miR-4298がhsa-miR-4298であり、miR-6786-5pがhsa-miR-6786-5pであり、miR-5010-5pがhsa-miR-5010-5pであり、miR-6087がhsa-miR-6087であり、miR-6765-5pがhsa-miR-6765-5pであり、miR-6732-5pがhsa-miR-6732-5pであり、miR-6787-5pがhsa-miR-6787-5pであり、miR-6737-5pがhsa-miR-6737-5pであり、miR-128-2-5pがhsa-miR-128-2-5pであり、miR-4270がhsa-miR-4270であり、miR-6861-5pがhsa-miR-6861-5pであり、miR-6756-5pがhsa-miR-6756-5pであり、miR-1229-5pがhsa-miR-1229-5pであり、miR-6891-5pがhsa-miR-6891-5pであり、miR-6848-5pがhsa-miR-6848-5pであり、miR-1237-5pがhsa-miR-1237-5pであり、miR-30c-1-3pがhsa-miR-30c-1-3pであり、miR-1233-5pがhsa-miR-1233-5pであり、miR-211-3pがhsa-miR-211-3pであり、miR-4758-5pがhsa-miR-4758-5pであり、miR-614がhsa-miR-614であり、miR-6746-5pがhsa-miR-6746-5pであり、miR-1915-5pがhsa-miR-1915-5pであり、miR-4688がhsa-miR-4688であり、miR-3917がhsa-miR-3917であり、miR-5787がhsa-miR-5787であり、miR-4632-5pがhsa-miR-4632-5pであり、miR-6126がhsa-miR-6126であり、miR-135a-3pがhsa-miR-135a-3pであり、miR-8063がhsa-miR-8063であり、miR-5698がhsa-miR-5698であり、miR-6089がhsa-miR-6089であり、miR-498がhsa-miR-498であり、miR-296-3pがhsa-miR-296-3pであり、miR-4419bがhsa-miR-4419bであり、miR-6802-5pがhsa-miR-6802-5pであり、miR-6829-5pがhsa-miR-6829-5pであり、miR-6803-5pがhsa-miR-6803-5pであり、miR-1199-5pがhsa-miR-1199-5pであり、miR-6840-3pがhsa-miR-6840-3pであり、miR-6752-5pがhsa-miR-6752-5pであり、miR-6798-5pがhsa-miR-6798-5pであり、miR-6131がhsa-miR-6131であり、miR-4667-5pがhsa-miR-4667-5pであり、miR-6510-5pがhsa-miR-6510-5pであり、miR-4690-5pがhsa-miR-4690-5pであり、miR-920がhsa-miR-920であり、miR-23b-3pがhsa-miR-23b-3pであり、miR-4448がhsa-miR-4448であり、miR-2110がhsa-miR-2110であり、miR-4706がhsa-miR-4706であり、miR-7845-5pがhsa-miR-7845-5pであり、miR-6808-5pがhsa-miR-6808-5pであり、miR-4447がhsa-miR-4447であり、miR-6869-5pがhsa-miR-6869-5pであり、miR-6794-5pがhsa-miR-6794-5pであり、miR-6511a-5pがhsa-miR-6511a-5pであり、miR-6824-5pがhsa-miR-6824-5pであり、miR-6766-3pがhsa-miR-6766-3pであり、miR-6511a-5pがhsa-miR-6511a-5pであり、miR-6749-5pがhsa-miR-6749-5pである、請求項1に記載のキット。
- 前記核酸が、下記の(a)~(e)のいずれかに示すポリヌクレオチド:
(a)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(b)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列を含むポリヌクレオチド、
(c)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(d)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列を含むポリヌクレオチド、及び
(e)前記(a)~(d)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択されるポリヌクレオチドである、請求項1又は2に記載のキット。 - 前記キットが、別の早期膵がん又は膵がん前駆病変マーカーである、miR-1908-5p、miR-6729-5p、miR-5195-3p、miR-638、miR-6125、miR-3178、miR-3196、miR-8069、miR-4723-5p、miR-4746-3p、miR-4689、miR-6816-5p、miR-6757-5p、miR-7109-5p、miR-6724-5p、miR-1225-3p、miR-6875-5p、miR-7108-5p、miR-4508、miR-6085、miR-6779-5p、miR-642a-3p、miR-4695-5p、miR-7847-3p、miR-3197、miR-6769b-5p、miR-7641、miR-187-5p、miR-3185、miR-2861、miR-3940-5p、miR-1203、miR-615-5p、miR-4787-5p、miR-1343-3p、miR-6813-5p、miR-1225-5p、miR-602、miR-4488、miR-125a-3p、miR-5100、miR-4294、miR-1231、miR-6765-3p、miR-4442、miR-718、miR-6780b-5p、miR-6090、miR-6845-5p、miR-4741、miR-4467、miR-4707-5p、miR-4271、miR-4673、miR-3184-5p、miR-1469、miR-4640-5p、miR-663a、miR-6791-5p、miR-6826-5p、miR-4433b-3p、miR-1915-3p、miR-4417、miR-4449、miR-4707-3p、miR-3180-3p、miR-5585-3p、miR-1268a、miR-8072、miR-296-5p、miR-204-3p、miR-4454、miR-6722-3p、miR-1290、miR-3622a-5p、miR-939-5p、miR-675-5p、miR-3131、miR-4648、miR-1268b、miR-6741-5p、miR-6893-5p、miR-3162-5p、miR-642b-3p、miR-4734、miR-150-3p、miR-8089、miR-6805-3p、miR-7113-3p、miR-6850-5p、miR-6799-5p、miR-6768-5p、miR-92b-5p、miR-3679-5p、miR-4792、miR-3656、miR-92a-2-5p、miR-4466、miR-4513、miR-6781-5p、miR-4649-5p、miR-6775-5p、miR-4651、miR-3195、miR-6726-5p、miR-6872-3p、miR-371a-5p、miR-6777-5p、miR-6789-5p、miR-7975、miR-6821-5p、miR-4534、miR-619-5p、miR-7107-5p、miR-1228-3p、miR-6774-5p、miR-6805-5p、miR-23a-3p、miR-4665-5p、miR-4505、miR-4638-5p、miR-24-3p、miR-3135b、miR-4745-5p、miR-128-1-5p、miR-4476、miR-4687-3p、miR-3665、miR-6806-5p、miR-3937、miR-711、miR-3141、miR-3188、miR-4281、miR-5196-5p、miR-6880-5p、miR-3960、miR-3648、miR-6721-5p、miR-4492、miR-744-5p、miR-7704、miR-4749-5p、miR-762、miR-6836-3p、miR-6727-5p、miR-4739、miR-7977、miR-4484、miR-6515-3p、miR-373-5p、miR-4258、miR-4674、miR-3180、miR-6076、miR-1238-5p、miR-4463、miR-4486、miR-4730、miR-4286、及び、miR-4739からなる群から選択される少なくとも1つのポリヌクレオチドと特異的に結合可能な核酸をさらに含む、請求項1~3のいずれか1項に記載のキット。
- miR-1908-5pがhsa-miR-1908-5pであり、miR-6729-5pがhsa-miR-6729-5pであり、miR-5195-3pがhsa-miR-5195-3pであり、miR-638がhsa-miR-638であり、miR-6125がhsa-miR-6125であり、miR-3178がhsa-miR-3178であり、miR-3196がhsa-miR-3196であり、miR-8069がhsa-miR-8069であり、miR-4723-5pがhsa-miR-4723-5pであり、miR-4746-3pがhsa-miR-4746-3pであり、miR-4689がhsa-miR-4689であり、miR-6816-5pがhsa-miR-6816-5pであり、miR-6757-5pがhsa-miR-6757-5pであり、miR-7109-5pがhsa-miR-7109-5pであり、miR-6724-5pがhsa-miR-6724-5pであり、miR-1225-3pがhsa-miR-1225-3pであり、miR-6875-5pがhsa-miR-6875-5pであり、miR-7108-5pがhsa-miR-7108-5pであり、miR-4508がhsa-miR-4508であり、miR-6085がhsa-miR-6085であり、miR-6779-5pがhsa-miR-6779-5pであり、miR-642a-3pがhsa-miR-642a-3pであり、miR-4695-5pがhsa-miR-4695-5pであり、miR-7847-3pがhsa-miR-7847-3pであり、miR-3197がhsa-miR-3197であり、miR-6769b-5pがhsa-miR-6769b-5pであり、miR-7641がhsa-miR-7641であり、miR-187-5pがhsa-miR-187-5pであり、miR-3185がhsa-miR-3185であり、miR-2861がhsa-miR-2861であり、miR-3940-5pがhsa-miR-3940-5pであり、miR-1203がhsa-miR-1203であり、miR-615-5pがhsa-miR-615-5pであり、miR-4787-5pがhsa-miR-4787-5pであり、miR-1343-3pがhsa-miR-1343-3pであり、miR-6813-5pがhsa-miR-6813-5pであり、miR-1225-5pがhsa-miR-1225-5pであり、miR-602がhsa-miR-602であり、miR-4488がhsa-miR-4488であり、miR-125a-3pがhsa-miR-125a-3pであり、miR-5100がhsa-miR-5100であり、miR-4294がhsa-miR-4294であり、miR-1231がhsa-miR-1231であり、miR-6765-3pがhsa-miR-6765-3pであり、miR-4442がhsa-miR-4442であり、miR-718がhsa-miR-718であり、miR-6780b-5pがhsa-miR-6780b-5pであり、miR-6090がhsa-miR-6090であり、miR-6845-5pがhsa-miR-6845-5pであり、miR-4741がhsa-miR-4741であり、miR-4467がhsa-miR-4467であり、miR-4707-5pがhsa-miR-4707-5pであり、miR-4271がhsa-miR-4271であり、miR-4673がhsa-miR-4673であり、miR-3184-5pがhsa-miR-3184-5pであり、miR-1469がhsa-miR-1469であり、miR-4640-5pがhsa-miR-4640-5pであり、miR-663aがhsa-miR-663aであり、miR-6791-5pがhsa-miR-6791-5pであり、miR-6826-5pがhsa-miR-6826-5pであり、miR-4433b-3pがhsa-miR-4433b-3pであり、miR-1915-3pがhsa-miR-1915-3pであり、miR-4417がhsa-miR-4417であり、miR-4449がhsa-miR-4449であり、miR-4707-3pがhsa-miR-4707-3pであり、miR-3180-3pがhsa-miR-3180-3pであり、miR-5585-3pがhsa-miR-5585-3pであり、miR-1268aがhsa-miR-1268aであり、miR-8072がhsa-miR-8072であり、miR-296-5pがhsa-miR-296-5pであり、miR-204-3pがhsa-miR-204-3pであり、miR-4454がhsa-miR-4454であり、miR-6722-3pがhsa-miR-6722-3pであり、miR-1290がhsa-miR-1290であり、miR-3622a-5pがhsa-miR-3622a-5pであり、miR-939-5pがhsa-miR-939-5pであり、miR-675-5pがhsa-miR-675-5pであり、miR-3131がhsa-miR-3131であり、miR-4648がhsa-miR-4648であり、miR-1268bがhsa-miR-1268bであり、miR-6741-5pがhsa-miR-6741-5pであり、miR-6893-5pがhsa-miR-6893-5pであり、miR-3162-5pがhsa-miR-3162-5pであり、miR-642b-3pがhsa-miR-642b-3pであり、miR-4734がhsa-miR-4734であり、miR-150-3pがhsa-miR-150-3pであり、miR-8089がhsa-miR-8089であり、miR-6805-3pがhsa-miR-6805-3pであり、miR-7113-3pがhsa-miR-7113-3pであり、miR-6850-5pがhsa-miR-6850-5pであり、miR-6799-5pがhsa-miR-6799-5pであり、miR-6768-5pがhsa-miR-6768-5pであり、miR-92b-5pがhsa-miR-92b-5pであり、miR-3679-5pがhsa-miR-3679-5pであり、miR-4792がhsa-miR-4792であり、miR-3656がhsa-miR-3656であり、miR-92a-2-5pがhsa-miR-92a-2-5pであり、miR-4466がhsa-miR-4466であり、miR-4513がhsa-miR-4513であり、miR-6781-5pがhsa-miR-6781-5pであり、miR-4649-5pがhsa-miR-4649-5pであり、miR-6775-5pがhsa-miR-6775-5pであり、miR-4651がhsa-miR-4651であり、miR-3195がhsa-miR-3195であり、miR-6726-5pがhsa-miR-6726-5pであり、miR-6872-3pがhsa-miR-6872-3pであり、miR-371a-5pがhsa-miR-371a-5pであり、miR-6777-5pがhsa-miR-6777-5pであり、miR-6789-5pがhsa-miR-6789-5pであり、miR-7975がhsa-miR-7975であり、miR-6821-5pがhsa-miR-6821-5pであり、miR-4534がhsa-miR-4534であり、miR-619-5pがhsa-miR-619-5pであり、miR-7107-5pがhsa-miR-7107-5pであり、miR-1228-3pがhsa-miR-1228-3pであり、miR-6774-5pがhsa-miR-6774-5pであり、miR-6805-5pがhsa-miR-6805-5pであり、miR-23a-3pがhsa-miR-23a-3pであり、miR-4665-5pがhsa-miR-4665-5pであり、miR-4505がhsa-miR-4505であり、miR-4638-5pがhsa-miR-4638-5pであり、miR-24-3pがhsa-miR-24-3pであり、miR-3135bがhsa-miR-3135bであり、miR-4745-5pがhsa-miR-4745-5pであり、miR-128-1-5pがhsa-miR-128-1-5pであり、miR-4476がhsa-miR-4476であり、miR-4687-3pがhsa-miR-4687-3pであり、miR-3665がhsa-miR-3665であり、miR-6806-5pがhsa-miR-6806-5pであり、miR-3937がhsa-miR-3937であり、miR-711がhsa-miR-711であり、miR-3141がhsa-miR-3141であり、miR-3188がhsa-miR-3188であり、miR-4281がhsa-miR-4281であり、miR-5196-5pがhsa-miR-5196-5pであり、miR-6880-5pがhsa-miR-6880-5pであり、miR-3960がhsa-miR-3960であり、miR-3648がhsa-miR-3648であり、miR-6721-5pがhsa-miR-6721-5pであり、miR-4492がhsa-miR-4492であり、miR-744-5pがhsa-miR-744-5pであり、miR-7704がhsa-miR-7704であり、miR-4749-5pがhsa-miR-4749-5pであり、miR-762がhsa-miR-762であり、miR-6836-3pがhsa-miR-6836-3pであり、miR-6727-5pがhsa-miR-6727-5pであり、miR-4739がhsa-miR-4739であり、miR-7977がhsa-miR-7977であり、miR-4484がhsa-miR-4484であり、miR-6515-3pがhsa-miR-6515-3pであり、miR-373-5pがhsa-miR-373-5pであり、miR-4258がhsa-miR-4258であり、miR-4674がhsa-miR-4674であり、miR-3180がhsa-miR-3180であり、miR-6076がhsa-miR-6076であり、miR-1238-5pがhsa-miR-1238-5pであり、miR-4463がhsa-miR-4463であり、miR-4486がhsa-miR-4486であり、miR-4730がhsa-miR-4730であり、miR-4286がhsa-miR-4286であり、miR-4739がhsa-miR-4739である、請求項4に記載のキット。
- 前記核酸が、下記の(f)~(j)のいずれかに示すポリヌクレオチド:
(f)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(g)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列を含むポリヌクレオチド、
(h)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(i)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列を含むポリヌクレオチド、及び
(j)前記(f)~(i)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択されるポリヌクレオチドである、請求項4又は5に記載のキット。 - 早期膵がん又は膵がん前駆病変マーカーである、miR-6784-5p、miR-1181、miR-671-5p、miR-6857-5p、miR-4276、miR-1914-3p、miR-149-3p、miR-937-5p、miR-4675、miR-6795-5p、miR-4731-5p、miR-5090、miR-3620-5p、miR-1343-5p、miR-6717-5p、miR-6825-5p、miR-6738-5p、miR-6769a-5p、miR-4728-5p、miR-652-5p、miR-4257、miR-6785-5p、miR-7110-5p、miR-6887-5p、miR-887-3p、miR-1228-5p、miR-5572、miR-6782-5p、miR-4298、miR-6786-5p、miR-5010-5p、miR-6087、miR-6765-5p、miR-6732-5p、miR-6787-5p、miR-6737-5p、miR-128-2-5p、miR-4270、miR-6861-5p、miR-6756-5p、miR-1229-5p、miR-6891-5p、miR-6848-5p、miR-1237-5p、miR-30c-1-3p、miR-1233-5p、miR-211-3p、miR-4758-5p、miR-614、miR-6746-5p、miR-1915-5p、miR-4688、miR-3917、miR-5787、miR-4632-5p、miR-6126、miR-135a-3p、miR-8063、miR-5698、miR-6089、miR-498、miR-296-3p、miR-4419b、miR-6802-5p、miR-6829-5p、miR-6803-5p、miR-1199-5p、miR-6840-3p、miR-6752-5p、miR-6798-5p、miR-6131、miR-4667-5p、miR-6510-5p、miR-4690-5p、miR-920、miR-23b-3p、miR-4448、miR-2110、miR-4706、miR-7845-5p、miR-6808-5p、miR-4447、miR-6869-5p、miR-6794-5p、miR-6511a-5p、miR-6824-5p、miR-6766-3p、miR-6511a-5p、及び、miR-6749-5pから選択される少なくとも1つのポリヌクレオチドと特異的に結合可能な核酸を含む、早期膵がん又は膵がん前駆病変の検出用デバイス。
- miR-6784-5pがhsa-miR-6784-5pであり、miR-1181がhsa-miR-1181であり、miR-671-5pがhsa-miR-671-5pであり、miR-6857-5pがhsa-miR-6857-5pであり、miR-4276がhsa-miR-4276であり、miR-1914-3pがhsa-miR-1914-3pであり、miR-149-3pがhsa-miR-149-3pであり、miR-937-5pがhsa-miR-937-5pであり、miR-4675がhsa-miR-4675であり、miR-6795-5pがhsa-miR-6795-5pであり、miR-4731-5pがhsa-miR-4731-5pであり、miR-5090がhsa-miR-5090であり、miR-3620-5pがhsa-miR-3620-5pであり、miR-1343-5pがhsa-miR-1343-5pであり、miR-6717-5pがhsa-miR-6717-5pであり、miR-6825-5pがhsa-miR-6825-5pであり、miR-6738-5pがhsa-miR-6738-5pであり、miR-6769a-5pがhsa-miR-6769a-5pであり、miR-4728-5pがhsa-miR-4728-5pであり、miR-652-5pがhsa-miR-652-5pであり、miR-4257がhsa-miR-4257であり、miR-6785-5pがhsa-miR-6785-5pであり、miR-7110-5pがhsa-miR-7110-5pであり、miR-6887-5pがhsa-miR-6887-5pであり、miR-887-3pがhsa-miR-887-3pであり、miR-1228-5pがhsa-miR-1228-5pであり、miR-5572がhsa-miR-5572であり、miR-6782-5pがhsa-miR-6782-5pであり、miR-4298がhsa-miR-4298であり、miR-6786-5pがhsa-miR-6786-5pであり、miR-5010-5pがhsa-miR-5010-5pであり、miR-6087がhsa-miR-6087であり、miR-6765-5pがhsa-miR-6765-5pであり、miR-6732-5pがhsa-miR-6732-5pであり、miR-6787-5pがhsa-miR-6787-5pであり、miR-6737-5pがhsa-miR-6737-5pであり、miR-128-2-5pがhsa-miR-128-2-5pであり、miR-4270がhsa-miR-4270であり、miR-6861-5pがhsa-miR-6861-5pであり、miR-6756-5pがhsa-miR-6756-5pであり、miR-1229-5pがhsa-miR-1229-5pであり、miR-6891-5pがhsa-miR-6891-5pであり、miR-6848-5pがhsa-miR-6848-5pであり、miR-1237-5pがhsa-miR-1237-5pであり、miR-30c-1-3pがhsa-miR-30c-1-3pであり、miR-1233-5pがhsa-miR-1233-5pであり、miR-211-3pがhsa-miR-211-3pであり、miR-4758-5pがhsa-miR-4758-5pであり、miR-614がhsa-miR-614であり、miR-6746-5pがhsa-miR-6746-5pであり、miR-1915-5pがhsa-miR-1915-5pであり、miR-4688がhsa-miR-4688であり、miR-3917がhsa-miR-3917であり、miR-5787がhsa-miR-5787であり、miR-4632-5pがhsa-miR-4632-5pであり、miR-6126がhsa-miR-6126であり、miR-135a-3pがhsa-miR-135a-3pであり、miR-8063がhsa-miR-8063であり、miR-5698がhsa-miR-5698であり、miR-6089がhsa-miR-6089であり、miR-498がhsa-miR-498であり、miR-296-3pがhsa-miR-296-3pであり、miR-4419bがhsa-miR-4419bであり、miR-6802-5pがhsa-miR-6802-5pであり、miR-6829-5pがhsa-miR-6829-5pであり、miR-6803-5pがhsa-miR-6803-5pであり、miR-1199-5pがhsa-miR-1199-5pであり、miR-6840-3pがhsa-miR-6840-3pであり、miR-6752-5pがhsa-miR-6752-5pであり、miR-6798-5pがhsa-miR-6798-5pであり、miR-6131がhsa-miR-6131であり、miR-4667-5pがhsa-miR-4667-5pであり、miR-6510-5pがhsa-miR-6510-5pであり、miR-4690-5pがhsa-miR-4690-5pであり、miR-920がhsa-miR-920であり、miR-23b-3pがhsa-miR-23b-3pであり、miR-4448がhsa-miR-4448であり、miR-2110がhsa-miR-2110であり、miR-4706がhsa-miR-4706であり、miR-7845-5pがhsa-miR-7845-5pであり、miR-6808-5pがhsa-miR-6808-5pであり、miR-4447がhsa-miR-4447であり、miR-6869-5pがhsa-miR-6869-5pであり、miR-6794-5pがhsa-miR-6794-5pであり、miR-6511a-5pがhsa-miR-6511a-5pであり、miR-6824-5pがhsa-miR-6824-5pであり、miR-6766-3pがhsa-miR-6766-3pであり、miR-6511a-5pがhsa-miR-6511a-5pであり、miR-6749-5pがhsa-miR-6749-5pである、請求項7に記載のデバイス。
- 前記核酸が、下記の(a)~(e)のいずれかに示すポリヌクレオチド:
(a)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(b)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列を含むポリヌクレオチド、
(c)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(d)配列番号1~83、227~229、246、248、及び250のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列を含むポリヌクレオチド、及び
(e)前記(a)~(d)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択されるポリヌクレオチドである、請求項7又は8に記載のデバイス。 - 前記デバイスが、別の早期膵がん又は膵がん前駆病変マーカーである、miR-1908-5p、miR-6729-5p、miR-5195-3p、miR-638、miR-6125、miR-3178、miR-3196、miR-8069、miR-4723-5p、miR-4746-3p、miR-4689、miR-6816-5p、miR-6757-5p、miR-7109-5p、miR-6724-5p、miR-1225-3p、miR-6875-5p、miR-7108-5p、miR-4508、miR-6085、miR-6779-5p、miR-642a-3p、miR-4695-5p、miR-7847-3p、miR-3197、miR-6769b-5p、miR-7641、miR-187-5p、miR-3185、miR-2861、miR-3940-5p、miR-1203、miR-615-5p、miR-4787-5p、miR-1343-3p、miR-6813-5p、miR-1225-5p、miR-602、miR-4488、miR-125a-3p、miR-5100、miR-4294、miR-1231、miR-6765-3p、miR-4442、miR-718、miR-6780b-5p、miR-6090、miR-6845-5p、miR-4741、miR-4467、miR-4707-5p、miR-4271、miR-4673、miR-3184-5p、miR-1469、miR-4640-5p、miR-663a、miR-6791-5p、miR-6826-5p、miR-4433b-3p、miR-1915-3p、miR-4417、miR-4449、miR-4707-3p、miR-3180-3p、miR-5585-3p、miR-1268a、miR-8072、miR-296-5p、miR-204-3p、miR-4454、miR-6722-3p、miR-1290、miR-3622a-5p、miR-939-5p、miR-675-5p、miR-3131、miR-4648、miR-1268b、miR-6741-5p、miR-6893-5p、miR-3162-5p、miR-642b-3p、miR-4734、miR-150-3p、miR-8089、miR-6805-3p、miR-7113-3p、miR-6850-5p、miR-6799-5p、miR-6768-5p、miR-92b-5p、miR-3679-5p、miR-4792、miR-3656、miR-92a-2-5p、miR-4466、miR-4513、miR-6781-5p、miR-4649-5p、miR-6775-5p、miR-4651、miR-3195、miR-6726-5p、miR-6872-3p、miR-371a-5p、miR-6777-5p、miR-6789-5p、miR-7975、miR-6821-5p、miR-4534、miR-619-5p、miR-7107-5p、miR-1228-3p、miR-6774-5p、miR-6805-5p、miR-23a-3p、miR-4665-5p、miR-4505、miR-4638-5p、miR-24-3p、miR-3135b、miR-4745-5p、miR-128-1-5p、miR-4476、miR-4687-3p、miR-3665、miR-6806-5p、miR-3937、miR-711、miR-3141、miR-3188、miR-4281、miR-5196-5p、miR-6880-5p、miR-3960、miR-3648、miR-6721-5p、miR-4492、miR-744-5p、miR-7704、miR-4749-5p、miR-762、miR-6836-3p、miR-6727-5p、miR-4739、miR-7977、miR-4484、miR-6515-3p、miR-373-5p、miR-4258、miR-4674、miR-3180、miR-6076、miR-1238-5p、miR-4463、miR-4486、miR-4730、miR-4286、及び、miR-4739からなる群から選択される少なくとも1つのポリヌクレオチドと特異的に結合可能な核酸をさらに含む、請求項7~9のいずれか1項に記載のデバイス。
- miR-1908-5pがhsa-miR-1908-5pであり、miR-6729-5pがhsa-miR-6729-5pであり、miR-5195-3pがhsa-miR-5195-3pであり、miR-638がhsa-miR-638であり、miR-6125がhsa-miR-6125であり、miR-3178がhsa-miR-3178であり、miR-3196がhsa-miR-3196であり、miR-8069がhsa-miR-8069であり、miR-4723-5pがhsa-miR-4723-5pであり、miR-4746-3pがhsa-miR-4746-3pであり、miR-4689がhsa-miR-4689であり、miR-6816-5pがhsa-miR-6816-5pであり、miR-6757-5pがhsa-miR-6757-5pであり、miR-7109-5pがhsa-miR-7109-5pであり、miR-6724-5pがhsa-miR-6724-5pであり、miR-1225-3pがhsa-miR-1225-3pであり、miR-6875-5pがhsa-miR-6875-5pであり、miR-7108-5pがhsa-miR-7108-5pであり、miR-4508がhsa-miR-4508であり、miR-6085がhsa-miR-6085であり、miR-6779-5pがhsa-miR-6779-5pであり、miR-642a-3pがhsa-miR-642a-3pであり、miR-4695-5pがhsa-miR-4695-5pであり、miR-7847-3pがhsa-miR-7847-3pであり、miR-3197がhsa-miR-3197であり、miR-6769b-5pがhsa-miR-6769b-5pであり、miR-7641がhsa-miR-7641であり、miR-187-5pがhsa-miR-187-5pであり、miR-3185がhsa-miR-3185であり、miR-2861がhsa-miR-2861であり、miR-3940-5pがhsa-miR-3940-5pであり、miR-1203がhsa-miR-1203であり、miR-615-5pがhsa-miR-615-5pであり、miR-4787-5pがhsa-miR-4787-5pであり、miR-1343-3pがhsa-miR-1343-3pであり、miR-6813-5pがhsa-miR-6813-5pであり、miR-1225-5pがhsa-miR-1225-5pであり、miR-602がhsa-miR-602であり、miR-4488がhsa-miR-4488であり、miR-125a-3pがhsa-miR-125a-3pであり、miR-5100がhsa-miR-5100であり、miR-4294がhsa-miR-4294であり、miR-1231がhsa-miR-1231であり、miR-6765-3pがhsa-miR-6765-3pであり、miR-4442がhsa-miR-4442であり、miR-718がhsa-miR-718であり、miR-6780b-5pがhsa-miR-6780b-5pであり、miR-6090がhsa-miR-6090であり、miR-6845-5pがhsa-miR-6845-5pであり、miR-4741がhsa-miR-4741であり、miR-4467がhsa-miR-4467であり、miR-4707-5pがhsa-miR-4707-5pであり、miR-4271がhsa-miR-4271であり、miR-4673がhsa-miR-4673であり、miR-3184-5pがhsa-miR-3184-5pであり、miR-1469がhsa-miR-1469であり、miR-4640-5pがhsa-miR-4640-5pであり、miR-663aがhsa-miR-663aであり、miR-6791-5pがhsa-miR-6791-5pであり、miR-6826-5pがhsa-miR-6826-5pであり、miR-4433b-3pがhsa-miR-4433b-3pであり、miR-1915-3pがhsa-miR-1915-3pであり、miR-4417がhsa-miR-4417であり、miR-4449がhsa-miR-4449であり、miR-4707-3pがhsa-miR-4707-3pであり、miR-3180-3pがhsa-miR-3180-3pであり、miR-5585-3pがhsa-miR-5585-3pであり、miR-1268aがhsa-miR-1268aであり、miR-8072がhsa-miR-8072であり、miR-296-5pがhsa-miR-296-5pであり、miR-204-3pがhsa-miR-204-3pであり、miR-4454がhsa-miR-4454であり、miR-6722-3pがhsa-miR-6722-3pであり、miR-1290がhsa-miR-1290であり、miR-3622a-5pがhsa-miR-3622a-5pであり、miR-939-5pがhsa-miR-939-5pであり、miR-675-5pがhsa-miR-675-5pであり、miR-3131がhsa-miR-3131であり、miR-4648がhsa-miR-4648であり、miR-1268bがhsa-miR-1268bであり、miR-6741-5pがhsa-miR-6741-5pであり、miR-6893-5pがhsa-miR-6893-5pであり、miR-3162-5pがhsa-miR-3162-5pであり、miR-642b-3pがhsa-miR-642b-3pであり、miR-4734がhsa-miR-4734であり、miR-150-3pがhsa-miR-150-3pであり、miR-8089がhsa-miR-8089であり、miR-6805-3pがhsa-miR-6805-3pであり、miR-7113-3pがhsa-miR-7113-3pであり、miR-6850-5pがhsa-miR-6850-5pであり、miR-6799-5pがhsa-miR-6799-5pであり、miR-6768-5pがhsa-miR-6768-5pであり、miR-92b-5pがhsa-miR-92b-5pであり、miR-3679-5pがhsa-miR-3679-5pであり、miR-4792がhsa-miR-4792であり、miR-3656がhsa-miR-3656であり、miR-92a-2-5pがhsa-miR-92a-2-5pであり、miR-4466がhsa-miR-4466であり、miR-4513がhsa-miR-4513であり、miR-6781-5pがhsa-miR-6781-5pであり、miR-4649-5pがhsa-miR-4649-5pであり、miR-6775-5pがhsa-miR-6775-5pであり、miR-4651がhsa-miR-4651であり、miR-3195がhsa-miR-3195であり、miR-6726-5pがhsa-miR-6726-5pであり、miR-6872-3pがhsa-miR-6872-3pであり、miR-371a-5pがhsa-miR-371a-5pであり、miR-6777-5pがhsa-miR-6777-5pであり、miR-6789-5pがhsa-miR-6789-5pであり、miR-7975がhsa-miR-7975であり、miR-6821-5pがhsa-miR-6821-5pであり、miR-4534がhsa-miR-4534であり、miR-619-5pがhsa-miR-619-5pであり、miR-7107-5pがhsa-miR-7107-5pであり、miR-1228-3pがhsa-miR-1228-3pであり、miR-6774-5pがhsa-miR-6774-5pであり、miR-6805-5pがhsa-miR-6805-5pであり、miR-23a-3pがhsa-miR-23a-3pであり、miR-4665-5pがhsa-miR-4665-5pであり、miR-4505がhsa-miR-4505であり、miR-4638-5pがhsa-miR-4638-5pであり、miR-24-3pがhsa-miR-24-3pであり、miR-3135bがhsa-miR-3135bであり、miR-4745-5pがhsa-miR-4745-5pであり、miR-128-1-5pがhsa-miR-128-1-5pであり、miR-4476がhsa-miR-4476であり、miR-4687-3pがhsa-miR-4687-3pであり、miR-3665がhsa-miR-3665であり、miR-6806-5pがhsa-miR-6806-5pであり、miR-3937がhsa-miR-3937であり、miR-711がhsa-miR-711であり、miR-3141がhsa-miR-3141であり、miR-3188がhsa-miR-3188であり、miR-4281がhsa-miR-4281であり、miR-5196-5pがhsa-miR-5196-5pであり、miR-6880-5pがhsa-miR-6880-5pであり、miR-3960がhsa-miR-3960であり、miR-3648がhsa-miR-3648であり、miR-6721-5pがhsa-miR-6721-5pであり、miR-4492がhsa-miR-4492であり、miR-744-5pがhsa-miR-744-5pであり、miR-7704がhsa-miR-7704であり、miR-4749-5pがhsa-miR-4749-5pであり、miR-762がhsa-miR-762であり、miR-6836-3pがhsa-miR-6836-3pであり、miR-6727-5pがhsa-miR-6727-5pであり、miR-4739がhsa-miR-4739であり、miR-7977がhsa-miR-7977であり、miR-4484がhsa-miR-4484であり、miR-6515-3pがhsa-miR-6515-3pであり、miR-373-5pがhsa-miR-373-5pであり、miR-4258がhsa-miR-4258であり、miR-4674がhsa-miR-4674であり、miR-3180がhsa-miR-3180であり、miR-6076がhsa-miR-6076であり、miR-1238-5pがhsa-miR-1238-5pであり、miR-4463がhsa-miR-4463であり、miR-4486がhsa-miR-4486であり、miR-4730がhsa-miR-4730であり、miR-4286がhsa-miR-4286であり、miR-4739がhsa-miR-4739である、請求項10に記載のデバイス。
- 前記核酸が、下記の(f)~(j)のいずれかに示すポリヌクレオチド:
(f)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(g)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列を含むポリヌクレオチド、
(h)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列からなるポリヌクレオチド、その変異体、その誘導体、又は15以上の連続した塩基を含むその断片、
(i)配列番号84~226、230~245、247、及び249のいずれかで表される塩基配列もしくは当該塩基配列においてuがtである塩基配列に相補的な塩基配列を含むポリヌクレオチド、及び
(j)前記(f)~(i)のいずれかのポリヌクレオチドとストリンジェントな条件でハイブリダイズするポリヌクレオチド、
からなる群から選択されるポリヌクレオチドである、請求項10又は11に記載のデバイス。 - 前記デバイスが、ハイブリダイゼーション技術による測定のためのデバイスである、請求項7~12のいずれか1項に記載のデバイス。
- 前記ハイブリダイゼーション技術が、核酸アレイ技術である、請求項13に記載のデバイス。
- 請求項1~6のいずれか1項に記載のキット又は請求項7~14のいずれか1項に記載のデバイスを用いて被験体の検体における標的核酸の発現量を測定し、該測定された発現量と、同様に測定された健常体の対照発現量とを用いて、被験体が早期膵がん又は膵がん前駆病変に罹患していること、又は早期膵がん又は膵がん前駆病変に罹患していないことをin vitroで評価し、それによって被験体における早期膵がん又は膵がん前駆病変の存在又は不存在を検出することを含む、被験体における早期膵がん又は膵がん前駆病変の検出方法。
- 請求項1~6のいずれか1項に記載のキット又は請求項7~14のいずれか1項に記載のデバイスを用いて被験体の検体における標的遺伝子の発現量を測定し、早期膵がん又は膵がん前駆病変を有することが既知である被験体由来の検体の遺伝子発現量と健常体由来の検体の遺伝子発現量を教師サンプルとして作成された、かつ早期膵がん又は膵がん前駆病変と健常とを区別的に判別することが可能である判別式に、上記被験体由来の検体中の標的遺伝子の発現量を代入し、それによって、早期膵がん又は膵がん前駆病変の存在又は不存在を評価することを含む、被験体における早期膵がん又は膵がん前駆病変を検出する方法。
- 前記被験体が、ヒトである、請求項15又は16に記載の方法。
- 前記検体が、血液、血清又は血漿である、請求項15~17のいずれか1項に記載の方法。
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KR20180129785A (ko) | 2018-12-05 |
JPWO2017171048A1 (ja) | 2019-02-14 |
EP3988668A2 (en) | 2022-04-27 |
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