WO2019208671A1 - 膀胱がんの検出のためのキット、デバイス及び方法 - Google Patents
膀胱がんの検出のためのキット、デバイス及び方法 Download PDFInfo
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Definitions
- the present invention relates to a kit or device for detecting bladder cancer comprising a nucleic acid capable of specifically binding to a specific miRNA or a complementary strand thereof, which is used for examining the presence or absence of bladder cancer in a subject. And a method for detecting bladder cancer comprising measuring the expression level of the miRNA.
- Urinary bladder is an organ in the pelvis, which acts as a kind of bag that temporarily stores urine produced by the kidney after it is transported through the renal pelvis and ureter. When the urinary bladder is stretched with accumulated urine, it feels like urine, and the muscles contract to work to urinate.
- the inner surface of the bladder is covered with transitional epithelial cells and is highly elastic.Bladder cancer is caused by the transitional epithelial cells becoming cancerous. It is known to account for 90%.
- Urinary epithelial cancer including bladder cancer, is a urological tumor that is frequently followed by prostate cancer, and the number of patients in Japan is about 16,000 in 2002, mainly elderly people. The prevalence rate is about 4 times higher for men than women.
- Smoking is known to play a major role in the development of bladder cancer, and occupational exposure to aromatic amines (exposure) is another established risk factor.
- bladder cancer When bladder cancer is classified according to T factor in the TNM classification used for evaluation of the degree of invasion, that is, the stage of disease, carcinoma in situ (Tis), superficial bladder cancer (Ta, T1), invasion in ascending order of invasion. It is classified into three types of primary bladder cancer (T2 or higher). Carcinoma in situ is known to be combined with superficial cancer and invasive cancer, or to occur in carcinoma in situ alone. It is known that there is an oversight even when an endoscopic examination, which is a definitive examination, is performed.
- Superficial bladder cancer is a cancer in which the invasion of cancer remains on the surface of the bladder, that is, the surface mucosa and the submucosa below it, and it rarely causes metastasis to other organs.
- Invasive bladder cancer is known to grow so that it extends to the muscles of the bladder and beyond the bladder, and metastasis is likely to occur. Also, the importance of early detection is particularly important because of the histological atypical grade of bladder cancer shown in High / Low grade, and high grade bladder cancer has high malignancy and is likely to metastasize early. high.
- bladder cancer The treatment of bladder cancer is determined in consideration of the degree of progression (Japan Urological Association, Japanese Pathology Society, Japanese Radiological Society, edited by the renal pelvis / ureter / bladder cancer treatment agreement, Kanehara Publishing, 2011), metastasis, and general condition,
- the standard treatment for bladder cancer is shown in (Japanese Urological Association / Edited Bladder Cancer Clinical Practice Guidelines, 2015 edition, published by medical books).
- the most common treatments are surgical resection (transurethral bladder tumor resection (TUR-BT), total cystectomy), radiation therapy, chemotherapy with anticancer drugs, and intravesical infusion of BCG.
- TUR-BT transurethral bladder tumor resection
- total cystectomy radiation therapy
- chemotherapy with anticancer drugs and intravesical infusion of BCG.
- cystoscopy is highly invasive and urine detects microscopically detached cancer cells.
- cytodiagnosis is a preferable method in terms of invasiveness, it has been reported that the specificity is about 94% and the sensitivity is 35% (Non-patent Document 1).
- Bladder cancer has a high recurrence rate and often recurs within 2 years.
- the recurrence rate after treatment is as high as 50-80%, of which 10-25% is detected as progressive invasive cancer in the muscle layer. It becomes important to extend
- Non-patent Document 1 Currently, several urine protein markers are available as noninvasive bladder cancer clinical laboratory markers. These marker tests are more sensitive than urine cytology. For example, in the NMP22 test that detects a specific nuclear matrix protein NuMA, the sensitivity is 47-100% and the specificity is 55-98% (Non-patent Document 1). The BTAtrak test for detecting a specific basement membrane fragment complex has a sensitivity of 60-83% and a specificity of 60-79% (Non-patent Document 1).
- markers using gene expression as an index miR-92a-2-5p, miR-150-3p, miR-1207-5p, miR-1202, miR-135a-3p, miR-1914 shown in Patent Document 1 are used. 3p, miR-1469, miR-149-3p, miR-663a, miR-1254, miR-1246, miR-92a-3p shown in Patent Document 2, miR-191-5p, miR shown in Non-Patent Document 2 -940, and miR-423-5p shown in Non-Patent Document 3 have been reported.
- urine cytology has a low sensitivity of 35%. This is because, among the histological atypical grades classified as High / Low, the Low grade is particularly difficult to distinguish, and depending on the type of specimen sample, the sensitivity may be low, and there is high variability among observers. Therefore, the problem remains in that it is not a universal inspection. In bladder endoscopy, the sensitivity is said to be as high as 90%, but it is actually an examination that depends on the subjectivity of the operator, and there are many cases where the differentiation from inflammation of the mucous membrane is subtle and unknown.
- the follow-up period is shortened and the conclusion is carried forward until the next cystoscopy, which may prove to be cancer, and there is a risk of oversight.
- bladder endoscopy is not anesthetized and is transurethrally observed, which is painful to the patient, especially for men because of the penis, which is a big pain and is a burden on unnecessary examination There is also.
- the above-mentioned existing protein and gene expression index are deficient in specificity and / or sensitivity, and have a large variation in measurement results depending on the timing of the test.
- An object of the present invention is to provide a disease diagnosis kit or device useful for diagnosis and treatment of bladder cancer in a non-invasive and small sample amount, and a bladder cancer determination (or detection) method.
- the present inventors have found a gene that can be used as a bladder cancer detection marker from blood that can be collected in a minimally invasive manner, and that this can be used to significantly detect bladder cancer. As a result, the present invention has been completed.
- the present invention includes the following aspects.
- polynucleotide according to any one of the following (a) to (e): (A) including a polynucleotide consisting of the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence in which u is t in the base sequence, a variant thereof, a derivative thereof, or 15 or more consecutive bases Its fragments, (B) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1-228, (C) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence complementary to the base sequence in which u is t in the base sequence, variants thereof, derivatives thereof, or 15 or more A fragment thereof containing a continuous base of (D) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 228 or a nucleotide sequence complementary to a nucleot
- the kit is another bladder cancer marker, miR-1220, miR-1207-5p, miR-1246, miR-1254, miR-135a-3p, miR-1469, miR-149-3p, at least selected from miR-150-3p, miR-1914-3p, miR-191-5p, miR-423-5p, miR-663a, miR-92a-2-5p, miR-92a-3p, miR-940
- the kit according to (1) or (2) further comprising a nucleic acid that can specifically bind to one polynucleotide or a complementary strand of the polynucleotide.
- bladder cancer markers miR-6087, miR-1185-1-3p, miR-1185-2-3p, miR-1193, miR-1199-5p, miR-1225-5p, miR-1227- 5p, miR-1228-3p, miR-1228-5p, miR-1237-5p, miR-1238-5p, miR-1247-3p, miR-1268a, miR-1268b, miR-1273g-3p, miR-128- 2-5p, miR-1343-3p, miR-1343-5p, miR-1470, miR-17-3p, miR-187-5p, miR-1908-3p, miR-1908-5p, miR-1909-3p, miR-1915-3p, miR-210-5p, miR-24-3p, miR-24 7-3p, miR-2861, miR-296-3p, miR-29b-3p, miR-3131, miR-3154, miR-3158-5p, miR-3160-5p, miR-3162-5p, miR-3178
- polynucleotide according to any one of the following (a) to (e): (A) including a polynucleotide consisting of the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence in which u is t in the base sequence, a variant thereof, a derivative thereof, or 15 or more consecutive bases Its fragments, (B) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1-228, (C) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence complementary to the base sequence in which u is t in the base sequence, variants thereof, derivatives thereof, or 15 or more A fragment thereof containing a continuous base of (D) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 228 or a nucleotide sequence complementary to a nucleo
- the device is another bladder cancer marker, miR-1220, miR-1207-5p, miR-1246, miR-1254, miR-135a-3p, miR-1469, miR-149-3p, at least selected from miR-150-3p, miR-1914-3p, miR-191-5p, miR-423-5p, miR-663a, miR-92a-2-5p, miR-92a-3p, miR-940
- the device according to (5) or (6) further comprising a nucleic acid that can specifically bind to one polynucleotide or a complementary strand of the polynucleotide.
- the expression level of the polynucleotide is measured using a nucleic acid capable of specifically binding to the polynucleotide or a complementary strand of the polynucleotide, and the nucleic acid is any of the following (a) to (e) Polynucleotides shown in: (A) including a polynucleotide consisting of the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence in which u is t in the base sequence, a variant thereof, a derivative thereof, or 15 or more consecutive bases Its fragments, (B) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1-228, (C) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence complementary to the base sequence in which u is t in the base sequence, variants thereof, derivatives thereof, or 15 or more A fragment thereof containing a continuous
- the expression level of the polynucleotide is measured using a nucleic acid that can specifically bind to the polynucleotide or a complementary strand of the polynucleotide, and the nucleic acid is any of the following (f) to (j) Polynucleotides shown in: (F) a polynucleotide comprising the nucleotide sequence represented by any of SEQ ID NOs: 229 to 243 or a nucleotide sequence in which u is t in the nucleotide sequence, a variant thereof, a derivative thereof, or 15 or more consecutive bases Its fragments, (G) a polynucleotide comprising the base sequence represented by any of SEQ ID NOS: 229 to 243, (H) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOS: 229 to 243 or a nucleotide sequence complementary to a nucleotide sequence in which
- 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, 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), cDNA, microRNA (miRNA), and fragments thereof, the human genome, and transcripts thereof.
- 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 orthologs), variants such as genetic polymorphisms, and “nucleic acids” encoding derivatives.
- nucleic acid encoding the homologue, variant or derivative is, for example, the base sequence represented by any one of SEQ ID NOs: 1 to 766 or the base sequence under stringent conditions described later
- nucleic acid having a base sequence that hybridizes with a complementary sequence of a base sequence in which u is t.
- 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 or “exosome” is a vesicle encapsulated in a lipid bilayer secreted from a cell. Exosomes are derived from multivesicular endosomes, and when released into 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, serum 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 used herein includes not only “miRNA” represented by a specific base sequence (or sequence number) but also a precursor of the “miRNA” (pre-miRNA, pri-miRNA).
- miRNAs that are biologically equivalent to the miRNAs encoded by them, such as homologues (ie, homologs or orthologs), variants such as genetic polymorphisms, and derivatives that encode derivatives.
- the “miRNA” encoding such precursor, homologue, variant or derivative can be specifically identified by miRBase release 21 (http://www.mirbase.org/) and described later. Examples thereof include “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 766 under stringent conditions.
- 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 continuous polynucleotide and / or a complementary polynucleotide that specifically recognizes and amplifies RNA generated by gene expression or a polynucleotide derived therefrom.
- a complementary polynucleotide (complementary strand, reverse strand) is a full-length sequence of a polynucleotide comprising a base sequence defined by any of SEQ ID NOs: 1 to 766 or a base sequence in which u is t in the base sequence , Or a partial sequence thereof (here, for convenience, this is referred to as a positive strand), a polynucleotide having a base complementary relationship based on a base pair relationship such as A: T (U), G: C Means.
- a complementary strand is not limited to the case where a complementary sequence is completely formed with the target positive-strand base sequence, but has a complementary relationship that allows hybridization with the target positive strand under stringent conditions. There may be.
- stringent conditions means that the nucleic acid probe is detectable to a greater extent than the other sequences (for example, average of background measurement values + standard error of background measurement values ⁇ 2 or more measurement values) ) 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 a double strand and a single strand are present at a ratio of 1: 1.
- variant refers to a natural variant caused by polymorphism, mutation, or the like, or a base sequence represented by a sequence number or a base in which u is t in the base sequence.
- a variant comprising a deletion, substitution, addition or insertion of 1, 2 or 3 or more (for example, 1 to several) bases in the sequence or a partial sequence thereof, or a precursor of any sequence of SEQ ID NOs: 1 to 243
- a mutant comprising deletion, substitution, addition or insertion of one or more bases in the nucleotide sequence of a prenatal miRNA, or in the nucleotide sequence where u is t in the nucleotide sequence, or in a partial sequence thereof, or the nucleotide sequence About 90% or more, about 95% or more, about 97% or more, about 98% or more, about 99% or more It refers to a polynucleotide or a nucleic acid which hybridises under stringent conditions of oligonucleotides as
- “several” means an integer of about 10, 9, 8, 7, 6, 5, 4, 3 or 2.
- a mutant can be prepared using a well-known technique such as a site-directed mutagenesis method or a mutagenesis method using a PCR method.
- % identity is based on BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) and FASTA (http://www.genome.jp/tools/fasta/).
- a protein or gene search system can be used to determine 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, Vol. 215, p403-410; Pearson, WR, et al., 1988, Proc. Natl. Acad. Sci. USA, Volume 85, p2444- 448).
- 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.
- derivatives 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) and the like.
- a “nucleic acid” capable of specifically binding to a polynucleotide selected from the above-mentioned bladder cancer marker miRNA or a complementary strand of the polynucleotide is a synthesized or prepared nucleic acid, specifically Includes a “nucleic acid probe” or “primer” to detect the presence or absence of bladder cancer in a subject, or whether or not there is a bladder cancer, whether there is an improvement in bladder cancer, It is used directly or indirectly to diagnose the degree of improvement, susceptibility to treatment of bladder cancer, or to screen candidate substances useful for prevention, improvement or treatment of bladder cancer.
- the term “detection” can be replaced by the term inspection, measurement, detection or decision 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 person” also means such a mammal that is not affected by the cancer to be detected.
- a preferable healthy person is a human.
- blade cancer is a malignant tumor that develops in the bladder, and includes urothelial cancer including renal pelvis and ureter.
- P or “P value” refers to the probability that, in a statistical test, a statistic that is 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 the value of (number of true positives) / (number of true positives + number of false negatives). High sensitivity makes it possible to detect bladder cancer at an early stage, 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 an unnecessary additional test by misidentifying a healthy person as a bladder cancer patient, thereby reducing the 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 changes the expression of the gene of the present invention as the bladder cancer develops, the bladder cancer progresses, and the therapeutic effect on the bladder cancer is exhibited.
- tissue and biomaterial Specifically, bladder tissue and renal pelvis, ureter, lymph node and surrounding organs, organs suspected of metastasis, skin, and body fluids such as blood, urine, saliva, sweat, tissue exudate, serum prepared from blood, It refers to plasma, other stool, hair and the like. Furthermore, it refers to a biological sample extracted from these, specifically genes such as RNA and miRNA.
- hsa-miR-6087 gene or “hsa-miR-6087” refers to the hsa-miR-6087 gene (miRBase Accession No. MIMAT0023712) described in SEQ ID NO: 1 or other biological species. Homologs or orthologs are included. The gene can be found in Yoo JK et al., 2012, Stem Cells Dev. 21, 2049-2057.
- hsa-miR-6087 “hsa-mir-6087” (miRBase Accession No. MI0020364, SEQ ID NO: 244) having a hairpin-like structure as a precursor is known.
- hsa-miR-1185-1-3p gene or “hsa-miR-1185-1-3p” as used herein refers to the hsa-miR-1185-1-3p described in SEQ ID NO: 2.
- Genes (miRBBase Accession No. MIMAT0022838) and other species homologues or orthologues are included. The gene is described in Berezikov E et al., 2006, Genome Res. 16, pp. 1299-1298.
- hsa-miR-1185-1-3p is known as “hsa-mir-1185-1” (miRBase Accession No. MI0003844, SEQ ID NO: 245) having a hairpin-like structure as a precursor.
- hsa-miR-1185-2-3p gene or “hsa-miR-1185-2-3p” as used herein refers to the hsa-miR-1185-2-3p described in SEQ ID NO: 3. Genes (miRBBase Accession No. MIMAT0022713) and other species homologues or orthologues are included. The gene is described in Berezikov E et al., 2006, Genome Res. 16, pp. 1299-1298. As for “hsa-miR-1185-2-3p”, “hsa-mir-1185-2” (miRBase Accession No. MI0003821, SEQ ID NO: 246) having a hairpin-like structure as a precursor is known.
- hsa-miR-1193 gene or “hsa-miR-1193” refers to the hsa-miR-1193 gene (miRBase Accession No. MIMAT0015049) described in SEQ ID NO: 4 and other biological species. Homologs or orthologs are included. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685. Also, “hsa-miR-1193” is known as “hsa-mir-1193” (miRBase Accession No. MI0014205, SEQ ID NO: 247) having a hairpin-like structure as a precursor.
- hsa-miR-1199-5p gene or “hsa-miR-1199-5p” refers to the hsa-miR-1199-5p gene (miRBase Accession No. 5) described in SEQ ID NO: 5. MIMAT0031119) and other species homologues or orthologues are included. The gene is described in Salvi A et al., 2013, Int J Oncol. 42, 391-402. As for “hsa-miR-1199-5p”, “hsa-mir-1199” (miRBase Accession No. MI0020340, SEQ ID NO: 248) having a hairpin-like structure as a precursor is known.
- hsa-miR-1225-5p gene or “hsa-miR-1225-5p” refers to the hsa-miR-1225-5p gene (miRBase Accession No. 6) described in SEQ ID NO: 6. MIMAT0005572) and other species homologues or orthologues are included. The gene is described in Berezikov E et al., 2007, Mol Cell. 28, 328-336. “Hsa-miR-1225-5p” is known as “hsa-mir-1225” (miRBase Accession No. MI0006311, SEQ ID NO: 249) having a hairpin-like structure as a precursor.
- hsa-miR-1227-5p gene or “hsa-miR-1227-5p” refers to the hsa-miR-1227-5p gene (miRBase Accession No. 7) described in SEQ ID NO: 7. MIMAT0022941) and other species homologs or orthologs are included. The gene is described in Berezikov E et al., 2007, Mol Cell. 28, 328-336. Also, “hsa-miR-1227-5p” is known as “hsa-mir-1227” (miRBase Accession No. MI0006316, SEQ ID NO: 250) having a hairpin-like structure as a precursor.
- hsa-miR-1228-3p gene or “hsa-miR-1228-3p” refers to the hsa-miR-1228-3p gene described in SEQ ID NO: 8 (miRBase Accession No. MIMAT0005583) and other species homologs or orthologs are included. The gene is described in Berezikov E et al., 2007, Mol Cell. 28, 328-336. Further, “hsa-miR-1228-3p” is known as “hsa-mir-1228” (miRBase Accession No. MI0006318, SEQ ID NO: 251) having a hairpin-like structure as a precursor.
- hsa-miR-1228-5p gene or “hsa-miR-1228-5p” refers to the hsa-miR-1228-5p gene described in SEQ ID NO: 9 (miRBase Accession No. MIMAT0005582) and other species homologues or orthologues are included. The gene is described in Berezikov E et al., 2007, Mol Cell. 28, 328-336. Also, “hsa-miR-1228-5p” is known as “hsa-mir-1228” (miRBase Accession No. MI0006318, SEQ ID NO: 252) having a hairpin-like structure as a precursor.
- hsa-miR-1237-5p gene or “hsa-miR-1237-5p” refers to the hsa-miR-1237-5p gene described in SEQ ID NO: 10 (miRBase Accession No. MIMAT0022946) and other species homologues or orthologues are included. The gene is described in Berezikov E et al., 2007, Mol Cell. 28, 328-336.
- hsa-miR-1237-5p is known as “hsa-mir-1237” (miRBase Accession No. MI0006327, SEQ ID NO: 253) having a hairpin-like structure as a precursor.
- hsa-miR-1238-5p gene or “hsa-miR-1238-5p” refers to the hsa-miR-1238-5p gene described in SEQ ID NO: 11 (miRBase Accession No. MIMAT0022947) and other species homologues or orthologues are included. The gene is described in Berezikov E et al., 2007, Mol Cell. 28, 328-336. Further, “hsa-miR-1238-5p” is known as “hsa-mir-1238” (miRBase Accession No. MI0006328, SEQ ID NO: 254) having a hairpin-like structure as a precursor.
- hsa-miR-1247-3p gene or “hsa-miR-1247-3p” refers to the hsa-miR-1247-3p gene (miRBase Accession No. 1) described in SEQ ID NO: 12. MIMAT0022721) and other species homologues or orthologues are included. The gene is described in Morin RD et al., 2008, Genome Res. 18, 610-621. “Hsa-miR-1247-3p” is known as “hsa-mir-1247” (miRBase Accession No. MI0006382, SEQ ID NO: 255), which has a hairpin-like structure as a precursor.
- hsa-miR-1268a gene or “hsa-miR-1268a” refers to the hsa-miR-1268a gene (miRBase Accession No. MIMAT0005922) described in SEQ ID NO: 13 and other biological species. Homologs or orthologs are included. The gene is described in Morin RD et al., 2008, Genome Res. 18, 610-621. “Hsa-miR-1268a” is known as “hsa-mir-1268a” (miRBase Accession No. MI0006405, SEQ ID NO: 256) 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: 14 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-1268b”, “hsa-mir-1268b” (miRBase Accession No. MI0016748, SEQ ID NO: 257) having a hairpin-like structure as a precursor is known.
- hsa-miR-1273g-3p gene or “hsa-miR-1273g-3p” refers to the hsa-miR-1273g-3p gene described in SEQ ID NO: 15 (miRBase Accession No. MIMAT0022742) and other species homologues or orthologues are included. The gene is described in Reshmi G et al., 2011, Genomics. 97, 333-340.
- hsa-miR-1273g-3p is known as “hsa-mir-1273g” (miRBase Accession No. MI0018003, SEQ ID NO: 258) having a hairpin-like structure as a precursor.
- 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: 16. Genes (miRBBase Accession No. MIMAT0031095) and other species homologues or orthologues are included. The gene is described in Lagos-Quintana M et al., 2002, Curr Biol. 12, Vol. 735-739. Further, “hsa-miR-128-2-5p” is known as “hsa-mir-128-2” (miRBase Accession No. MI000027, SEQ ID NO: 259) 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: 17 (miRBase Accession No. MIMAT0019776) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-1343-3p “hsa-mir-1343” (miRBase Accession No. MI0017320, SEQ ID NO: 260) 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: 18 (miRBase Accession No. 1). MIMAT0027038) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-1343-5p” “hsa-mir-1343” (miRBase Accession No. MI0017320, SEQ ID NO: 261) having a hairpin-like structure as a precursor is known.
- hsa-miR-1470 gene or “hsa-miR-1470” refers to the hsa-miR-1470 gene (miRBase Accession No. MIMAT0007348) described in SEQ ID NO: 19 and other biological species. A homolog or ortholog is included. The gene is described in Kawaji H et al., 2008, BMC Genomics. , Vol. 9, 157. Also, “hsa-miR-1470” is known as “hsa-mir-1470” (miRBase Accession No. MI00000075, SEQ ID NO: 262) having a hairpin-like structure as a precursor.
- hsa-miR-17-3p gene or “hsa-miR-17-3p” refers to the hsa-miR-17-3p gene described in SEQ ID NO: 20 (miRBase Accession No. MIMAT0000071) and other species homologs or orthologs. The gene is described in Lagos-Quintana M et al., 2001, Science. 294, 853-858.
- hsa-miR-17-3p “hsa-mir-17” (miRBase Accession No. MI0000071, SEQ ID NO: 263) having a hairpin-like structure as a precursor 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: 21 (miRBase Accession No. MIMAT0004561) and other species homologs or orthologs are included. The gene is described in Lim LP et al., 2003, Science. 299, 1540. Further, “hsa-miR-187-5p” is known as “hsa-mir-187” (miRBase Accession No. MI00000027, SEQ ID NO: 264) having a hairpin-like structure as a precursor.
- hsa-miR-1908-3p gene or “hsa-miR-1908-3p” refers to the hsa-miR-1908-3p gene described in SEQ ID NO: 22 (miRBase Accession No. MIMAT0026916) and other species homologs or orthologs. The gene is described in Bar M et al., 2008, Stem Cells. 26, 2496-2505.
- hsa-miR-1908-3p “hsa-mir-1908” (miRBase Accession No. MI0008329, SEQ ID NO: 265) 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 (miRBase Accession No. MIMAT0007881) and other species homologues or orthologues are included. The gene is described in Bar M et al., 2008, Stem Cells. 26, 2496-2505. As for “hsa-miR-1908-5p”, “hsa-mir-1908” (miRBase Accession No. MI0008329, SEQ ID NO: 266) having a hairpin-like structure as a precursor is known.
- hsa-miR-1909-3p gene or “hsa-miR-1909-3p” refers to the hsa-miR-1909-3p gene described in SEQ ID NO: 24 (miRBase Accession No. MIMAT0007883) and other species homologs or orthologs. The gene is described in Bar M et al., 2008, Stem Cells. 26, 2496-2505.
- hsa-miR-1909-3p “hsa-mir-1909” (miRBase Accession No. MI0008330, SEQ ID NO: 267) having a hairpin-like structure as a precursor is known.
- hsa-miR-1915-3p gene or “hsa-miR-1915-3p” refers to the hsa-miR-1915-3p gene described in SEQ ID NO: 25 (miRBase Accession No. MIMAT0007892) and other species homologues or orthologues are included. The gene is described in Bar M et al., 2008, Stem Cells. 26, 2496-2505.
- hsa-miR-1915-3p “hsa-mir-1915” (miRBase Accession No. MI0008336, SEQ ID NO: 268) having a hairpin-like structure as a precursor is known.
- hsa-miR-210-5p gene or “hsa-miR-210-5p” refers to the hsa-miR-210-5p gene described in SEQ ID NO: 26 (miRBase Accession No. MIMAT0026475) and other species homologs or orthologs. The gene is described in Lim LP et al., 2003, Science. 299, 1540.
- hsa-miR-210-5p “hsa-mir-210” (miRBase Accession No. MI00000028, SEQ ID NO: 269) 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: 27 (miRBase Accession No. MIMAT00000080) and other species homologs or orthologs. The gene is described in Lagos-Quintana M et al., 2001, Science. 294, 853-858.
- “Hsa-miR-24-3p” has a hairpin-like structure as a precursor thereof, “hsa-mir-24-1” (miRBase Accession No. MI00000080, SEQ ID NO: 472), and “hsa-mir-24” -2 "(miRBBase Accession No. MI00000081, SEQ ID NO: 484) is known.
- hsa-miR-2467-3p gene or “hsa-miR-2467-3p” refers to the hsa-miR-2467-3p gene described in SEQ ID NO: 28 (miRBase Accession No. MIMAT0019953) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-2467-3p “hsa-mir-2467” (miRBase Accession No. MI0017432, SEQ ID NO: 270) 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: 29 and other biological species. Homologs or orthologs are included. The gene is described in Li H et al., 2009, J Clin Invest. 119, 3666-3777.
- hsa-miR-2861 “hsa-mir-2861” (miRBase Accession No. MI0013006, SEQ ID NO: 271) having a hairpin-like structure as a precursor is known.
- hsa-miR-296-3p gene or “hsa-miR-296-3p” refer to the hsa-miR-296-3p gene described in SEQ ID NO: 30 (miRBase Accession No. MIMAT0004679) and other species homologs or orthologs. The gene is described in Houbavy HB et al., 2003, Dev Cell. No. 5, 351-358. Also, “hsa-miR-296-3p” is known as “hsa-mir-296” (miRBase Accession No. MI000047, SEQ ID NO: 272), which has a hairpin-like structure as a precursor.
- hsa-miR-29b-3p gene or “hsa-miR-29b-3p” refers to the hsa-miR-29b-3p gene described in SEQ ID NO: 31 (miRBase Accession No. MIMAT0000100) and other species homologs or orthologs. The gene is described in Mouretos Z et al., 2002, Genes Dev. 16, 720-728. “Hsa-miR-29b-3p” has a hairpin-like structure as a precursor thereof, “hsa-mir-29b-1” (miRBase Accession No. MI0000105, SEQ ID NO: 473), and “hsa-mir-29b”. -2 "(miRBBase Accession No. MI0000107, SEQ ID NO: 485) 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: 32 or other species. Homologs or orthologs are included. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685. As for “hsa-miR-3131”, “hsa-mir-3131” (miRBase Accession No. MI0014151, SEQ ID NO: 273) having a hairpin-like structure as a precursor is known.
- hsa-miR-3154 gene or “hsa-miR-3154” refers to the hsa-miR-3154 gene (miRBase Accession No. MIMAT0015028) described in SEQ ID NO: 33 and other biological species. Homologs or orthologs are included. The gene is described in Berezikov E et al., 2006, Genome Res. 16, pp. 1299-1298. As for “hsa-miR-3154”, “hsa-mir-3154” (miRBase Accession No. MI0014182, SEQ ID NO: 274) having a hairpin-like structure as a precursor is known.
- hsa-miR-3158-5p gene or “hsa-miR-3158-5p” refers to the hsa-miR-3158-5p gene described in SEQ ID NO: 34 (miRBase Accession No. MIMAT0019211) and other species homologues or orthologues are included. The gene is described in Creighton CJ et al., 2010, PLoS One. 5, Vol. 5, e9637. “Hsa-miR-3158-5p” has a hairpin-like structure as a precursor thereof, “hsa-mir-3158-1” (miRBase Accession No. MI0014186, SEQ ID NO: 474), and “hsa-mir-3158” -2 "(miRBBase Accession No. MI0014187, SEQ ID NO: 486) is known.
- hsa-miR-3160-5p gene or “hsa-miR-3160-5p” refers to the hsa-miR-3160-5p gene (miRBase Accession No. 5) described in SEQ ID NO: 35. MIMAT0019212) and other species homologues or orthologues are included. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685. “Hsa-miR-3160-5p” has a hairpin-like structure as its precursor, “hsa-mir-3160-1” (miRBase Accession No. MI0014189, SEQ ID NO: 475), and “hsa-mir-3160” -2 "(miRBBase Accession No. MI0014190, SEQ ID NO: 487) 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: 36 (miRBase Accession No. MIMAT0015036) and other species homologs or orthologs. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685. As for “hsa-miR-3162-5p”, “hsa-mir-3162” (miRBase Accession No. MI0014192, SEQ ID NO: 275) 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: 37 and other biological species. Homologs or orthologs are included. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685. As for “hsa-miR-3178”, “hsa-mir-3178” (miRBase Accession No. MI0014212, SEQ ID NO: 276) having a hairpin-like structure as a precursor is known.
- hsa-miR-3180-3p gene or “hsa-miR-3180-3p” refer to the hsa-miR-3180-3p gene described in SEQ ID NO: 38 (miRBase Accession No. MIMAT0015058) and other species homologs or orthologs. The gene is described in Creighton CJ et al., 2010, PLoS One. 5, Vol. 5, e9637. “Hsa-miR-3180-3p” has a hairpin-like structure as a precursor thereof, “hsa-mir-3180-1” (miRBase Accession No.
- hsa-miR-3184-5p gene or “hsa-miR-3184-5p” refers to the hsa-miR-3184-5p gene described in SEQ ID NO: 39 (miRBase Accession No. MIMAT0015064) and other species homologs or orthologs. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685.
- hsa-miR-3184-5p is known as “hsa-mir-3184” (miRBase Accession No. MI0014226, SEQ ID NO: 277) 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: 40 or other biological species. Homologs or orthologs are included. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685. As for “hsa-miR-3185”, “hsa-mir-3185” (miRBase Accession No. MI0014227, SEQ ID NO: 278) having a hairpin-like structure as a precursor is known.
- hsa-miR-3194-3p gene or “hsa-miR-3194-3p” refers to the hsa-miR-3194-3p gene described in SEQ ID NO: 41 (miRBase Accession No. MIMAT0019218) and other species homologs or orthologs are included. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685. Further, “hsa-miR-3194-3p” is known as “hsa-mir-3194” (miRBase Accession No. MI0014239, SEQ ID NO: 279) 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: 42 or other biological species. Homologs or orthologs are included. The gene is described in Stark MS et al., 2010, PLoS One. No. 5, vol. E9685. As for “hsa-miR-3195”, “hsa-mir-3195” (miRBase Accession No. MI0014240, SEQ ID NO: 280) having a hairpin-like structure as a precursor is known.
- hsa-miR-3197 gene or “hsa-miR-3197” refers to the hsa-miR-3197 gene (miRBase Accession No. MIMAT0015082) described in SEQ ID NO: 43 or other biological species. Homologs or orthologs are included. The gene is described in Stark MS et al., 2010, PLoS One. 5 and can be obtained by the method described in e9685. As for “hsa-miR-3197”, “hsa-mir-3197” (miRBase Accession No. MI0014245, SEQ ID NO: 281) having a hairpin-like structure as a precursor is known.
- hsa-miR-320a gene or “hsa-miR-320a” refers to the hsa-miR-320a gene (miRBase Accession No. MIMAT000010) described in SEQ ID NO: 44 and other biological species. Homologs or orthologs are included. The gene is described in Michael MZ et al., 2003, Mol Cancer Res. 1, 882-891. As for “hsa-miR-320a”, “hsa-mir-320a” (miRBase Accession No. MI000042, SEQ ID NO: 282) having a hairpin-like structure as a precursor is known.
- hsa-miR-320b gene or “hsa-miR-320b” refers to the hsa-miR-320b gene (miRBase Accession No. MIMAT0005792) described in SEQ ID NO: 45 and other biological species. Homologs or orthologs are included. The gene is described in Berezikov E et al., 2006, Genome Res. 16, pp. 1299-1298. “Hsa-miR-320b” has a hairpin-like structure as its precursor, “hsa-mir-320b-1” (miRBase Accession No. MI0003776, SEQ ID NO: 476), and “hsa-mir-320b-2” (MiRBBase Accession No. MI0003839, SEQ ID NO: 488) is known.
- hsa-miR-328-5p gene or “hsa-miR-328-5p” refers to the hsa-miR-328-5p gene described in SEQ ID NO: 46 (miRBase Accession No. MIMAT0026486) and other species homologues or orthologues are included. The gene was found in Kim J et al., 2004, Proc Natl Acad Sci USA. 101, 360-365. Further, “hsa-miR-328-5p” is known as “hsa-mir-328” (miRBase Accession No. MI000004, SEQ ID NO: 283) having a hairpin-like structure as a precursor.
- hsa-miR-342-5p gene or “hsa-miR-342-5p” refers to the hsa-miR-342-5p gene described in SEQ ID NO: 47 (miRBase Accession No. MIMAT0004694) and other species homologues or orthologues are included. The gene was found in Kim J et al., 2004, Proc Natl Acad Sci USA. 101, 360-365. Also, “hsa-miR-342-5p” is known as “hsa-mir-342” (miRBase Accession No. MI000005, SEQ ID NO: 284) having a hairpin-like structure as a precursor.
- hsa-miR-345-3p gene or “hsa-miR-345-3p” refers to the hsa-miR-345-3p gene described in SEQ ID NO: 48 (miRBase Accession No. MIMAT0022698) and other species homologs or orthologs. The gene was found in Kim J et al., 2004, Proc Natl Acad Sci USA. 101, 360-365.
- hsa-miR-345-3p “hsa-mir-345” (miRBase Accession No. MI000025, SEQ ID NO: 285) having a hairpin-like structure as a precursor is known.
- hsa-miR-3616-3p gene or “hsa-miR-3616-3p” refers to the hsa-miR-3616-3p gene described in SEQ ID NO: 49 (miRBase Accession No. MIMAT0017996) and other species homologues or orthologues are included. The gene is described in Witten D et al., 2010, BMC Biol. , 8, 58.
- hsa-miR-3616-3p “hsa-mir-3616” (miRBase Accession No. MI0016006, SEQ ID NO: 286) having a hairpin-like structure as a precursor is known.
- hsa-miR-3619-3p gene or “hsa-miR-3619-3p” refers to the hsa-miR-3619-3p gene described in SEQ ID NO: 50 (miRBase Accession No. MIMAT0019219) and other species homologues or orthologues are included. The gene is described in Witten D et al., 2010, BMC Biol. , 8, 58.
- “hsa-miR-3619-3p” is known as “hsa-mir-3619” (miRBase Accession No. MI0016009, SEQ ID NO: 287) having a hairpin-like structure as a precursor.
- hsa-miR-3620-5p gene or “hsa-miR-3620-5p” refers to the hsa-miR-3620-5p gene described in SEQ ID NO: 51 (miRBase Accession No. MIMAT0022967) and other species homologs or orthologs. The gene is described in Witten D et al., 2010, BMC Biol. , 8, 58.
- hsa-miR-3620-5p “hsa-mir-3620” (miRBase Accession No. MI0016011, SEQ ID NO: 288) having a hairpin-like structure as a precursor is known.
- hsa-miR-3621 gene or “hsa-miR-3621” refers to the hsa-miR-3621 gene (miRBase Accession No. MIMAT0018002) described in SEQ ID NO: 52 or other biological species. Homologs or orthologs are included. The gene is described in Witten D et al., 2010, BMC Biol. , 8, 58.
- hsa-miR-3621 “hsa-mir-3621” (miRBase Accession No. MI0016012, SEQ ID NO: 289) 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: 53 (miRBase Accession No. MIMAT0018003) and other species homologs or orthologs. The gene is described in Witten D et al., 2010, BMC Biol. , 8, 58.
- “hsa-miR-3622a-5p” “hsa-mir-3622a” (miRBase Accession No. MI0016013, SEQ ID NO: 290) 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: 54 and other biological species. Homologs or orthologs are included. The gene is described in Meiri E et al., 2010, Nucleic Acids Res. 38, 6234-6246. “Hsa-miR-3648” has a hairpin-like structure as its precursor, “hsa-mir-3648-1” (miRBase Accession No. MI0016048, SEQ ID NO: 477), and “hsa-mir-3648-2” (MiRBBase Accession No. MI0031512, SEQ ID NO: 489) is known.
- hsa-miR-3652 gene or “hsa-miR-3652” refers to the hsa-miR-3652 gene (miRBase Accession No. MIMAT0018072) described in SEQ ID NO: 55 and other biological species. Homologs or orthologs are included. The gene is described in Meiri E et al., 2010, Nucleic Acids Res. 38, 6234-6246. “Hsa-miR-3652” is known as “hsa-mir-3652” (miRBase Accession No. MI0016052, SEQ ID NO: 291) having a hairpin-like structure as a precursor.
- hsa-miR-3656 gene or “hsa-miR-3656” refers to the hsa-miR-3656 gene (miRBase Accession No. MIMAT0018076) described in SEQ ID NO: 56 and other biological species. Homologs or orthologs are included. The gene is described in Meiri E et al., 2010, Nucleic Acids Res. 38, 6234-6246. Also, “hsa-miR-3656” is known as “hsa-mir-3656” (miRBase Accession No. MI0016056, SEQ ID NO: 292) having a hairpin-like structure as a precursor.
- hsa-miR-3663-3p gene or “hsa-miR-3663-3p” refers to the hsa-miR-3663-3p gene described in SEQ ID NO: 57 (miRBase Accession No. MIMAT0018085) and other species homologs or orthologs. The gene is described in Liao JY et al., 2010, PLoS One. 5, Vol. 5, e10563. Also, “hsa-miR-3663-3p” is known as “hsa-mir-3663” (miRBase Accession No. MI0016064, SEQ ID NO: 293) having a hairpin-like structure as a precursor.
- hsa-miR-3679-5p gene or “hsa-miR-3679-5p” refers to the hsa-miR-3679-5p gene described in SEQ ID NO: 58 (miRBase Accession No. MIMAT0018104) and other species homologues or orthologues are included. The gene is described in Creighton CJ et al., 2010, PLoS One. 5, Vol. 5, e9637. Further, “hsa-miR-3679-5p” is known as “hsa-mir-3679” (miRBase Accession No. MI0016080, SEQ ID NO: 294) having a hairpin-like structure as a precursor.
- hsa-miR-371b-5p gene or “hsa-miR-371b-5p” refers to the hsa-miR-371b-5p gene described in SEQ ID NO: 59 (miRBase Accession No. MIMAT0019892) and other species homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-371b-5p”, “hsa-mir-371b” (miRBase Accession No. MI0017393, SEQ ID NO: 295) 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: 60 (miRBase Accession No. MIMAT000025) and other species homologues or orthologues are included. The gene is described in Suh MR et al., 2004, Dev Biol. 270, 488-498.
- hsa-miR-373-5p “hsa-mir-373” (miRBase Accession No. MI0000811, SEQ ID NO: 296) having a hairpin-like structure as a precursor is known.
- hsa-miR-3717 gene or “hsa-miR-3919” refers to the hsa-miR-3717 gene (miRBase Accession No. MIMAT0018191) described in SEQ ID NO: 61 or other biological species. Homologs or orthologs are included. The gene is described in Creighton CJ et al., 2010, PLoS One. 5, Vol. 5, e9637.
- hsa-miR-3917 is known as “hsa-mir-3917” (miRBase Accession No. MI0016423, SEQ ID NO: 297) having a hairpin-like structure as a precursor.
- hsa-miR-3940-5p gene or “hsa-miR-3940-5p” refers to the hsa-miR-3940-5p gene (miRBase Accession No. MIMAT0019229) and other species homologues or orthologues are included. The gene is described in Liao JY et al., 2010, PLoS One. 5, Vol. 5, e10563.
- hsa-miR-3940-5p is known as “hsa-mir-3940” (miRBase Accession No. MI0016597, SEQ ID NO: 298) having a hairpin-like structure as a precursor.
- hsa-miR-3960 gene or “hsa-miR-3960” refers to the hsa-miR-3960 gene (miRBase Accession No. MIMAT0019337) described in SEQ ID NO: 63 or other biological species. Homologs or orthologs are included. The gene is described in Hu R et al., 2011, J Biol Chem. 286, 12328-12339. As for “hsa-miR-3960”, “hsa-mir-3960” (miRBase Accession No. MI0016964, SEQ ID NO: 299) 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: 64 and other biological species. Homologs or orthologs are included. The gene is Goff LA et al., 2009, PLoS One. 4, Volume 4, e7192.
- hsa-miR-4258 “hsa-mir-4258” (miRBase Accession No. MI0015857, SEQ ID NO: 300) having a hairpin-like structure as a precursor is known.
- hsa-miR-4259 gene or “hsa-miR-4259” refers to the hsa-miR-4259 gene (miRBase Accession No. MIMAT0016880) described in SEQ ID NO: 65 and other biological species. Homologs or orthologs are included. The gene is Goff LA et al., 2009, PLoS One. 4, Volume 4, e7192.
- “hsa-miR-4259” is known as “hsa-mir-4259” (miRBase Accession No. MI0015858, SEQ ID NO: 301) 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: 66 and other biological species. Homologs or orthologs are included. The gene is Goff LA et al., 2009, PLoS One. 4, Volume 4, e7192.
- hsa-miR-4270 “hsa-mir-4270” (miRBase Accession No. MI0015878, SEQ ID NO: 302) 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: 67 and other biological species. Homologs or orthologs are included. The gene is Goff LA et al., 2009, PLoS One. 4, Volume 4, e7192.
- hsa-miR-4286 is known as “hsa-mir-4286” (miRBase Accession No. MI0015894, SEQ ID NO: 303) having a hairpin-like structure as a precursor.
- hsa-miR-4298 gene or “hsa-miR-4298” refers to the hsa-miR-4298 gene (miRBase Accession No. MIMAT0016852) described in SEQ ID NO: 68 and other biological species. Homologs or orthologs are included. The gene is Goff LA et al., 2009, PLoS One. 4, Volume 4, e7192. Also, “hsa-miR-4298” is known as “hsa-mir-4298” (miRBase Accession No. MI0015830, SEQ ID NO: 304) having a hairpin-like structure as a precursor.
- hsa-miR-4322 gene or “hsa-miR-4322” refers to the hsa-miR-4322 gene (miRBase Accession No. MIMAT0016873) described in SEQ ID NO: 69 or other biological species. Homologs or orthologs are included. The gene is Goff LA et al., 2009, PLoS One. 4, Volume 4, e7192.
- “hsa-miR-4322” is known as “hsa-mir-4322” (miRBase Accession No. MI0015851, SEQ ID NO: 305) having a hairpin-like structure as a precursor.
- hsa-miR-4327 gene or “hsa-miR-4327” refers to the hsa-miR-4327 gene (miRBase Accession No. MIMAT0016889) described in SEQ ID NO: 70 or other biological species. Homologs or orthologs are included. The gene is Goff LA et al., 2009, PLoS One. 4, Volume 4, e7192. Further, “hsa-miR-4327” is known as “hsa-mir-4327” (miRBase Accession No. MI0015867, SEQ ID NO: 306) having a hairpin-like structure as a precursor.
- hsa-miR-4417 gene or “hsa-miR-4417” refers to the hsa-miR-4417 gene (miRBase Accession No. MIMAT0018929) described in SEQ ID NO: 71 and other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. “Hsa-miR-4417” is known as “hsa-mir-4417” (miRBase Accession No. MI0016753, SEQ ID NO: 307) 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: 72 and other species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4419b”, “hsa-mir-4419b” (miRBase Accession No. MI0016861, SEQ ID NO: 308) having a hairpin-like structure as a precursor is known.
- hsa-miR-4429 gene or “hsa-miR-4429” refers to the hsa-miR-4429 gene (miRBase Accession No. MIMAT0018944) described in SEQ ID NO: 73 and other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4429”, “hsa-mir-4429” (miRBase Accession No. MI0016768, SEQ ID NO: 309) having a hairpin-like structure as a precursor is known.
- hsa-miR-4430 gene or “hsa-miR-4430” refers to the hsa-miR-4430 gene (miRBase Accession No. MIMAT0018945) described in SEQ ID NO: 74 and other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127.
- hsa-miR-4430 “hsa-mir-4430” (miRBase Accession No. MI0016769, SEQ ID NO: 310) having a hairpin-like structure as a precursor is known.
- hsa-miR-4433a-3p gene or “hsa-miR-4433a-3p” refers to the hsa-miR-4433a-3p gene described in SEQ ID NO: 75 (miRBase Accession No. MIMAT0018949) and other species homologs or orthologs. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127.
- hsa-mir-4433a miRBase Accession No. MI0016773, SEQ ID NO: 311) having a hairpin-like structure as a precursor is known.
- hsa-miR-4436b-5p gene or “hsa-miR-4436b-5p” refers to the hsa-miR-4436b-5p gene described in SEQ ID NO: 76 (miRBase Accession No. MIMAT0019940) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. “Hsa-miR-4436b-5p” has a hairpin-like structure as a precursor thereof, “hsa-mir-4436b-1” (miRBase Accession No. MI0017425, SEQ ID NO: 478), and “hsa-mir-4436b”. -2 "(miRBBase Accession No. MI0019110, SEQ ID NO: 490) is known.
- hsa-miR-4443 gene or “hsa-miR-4443” refers to the hsa-miR-4443 gene (miRBase Accession No. MIMAT0018961) described in SEQ ID NO: 77 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. Further, “hsa-miR-4443” is known as “hsa-mir-4443” (miRBase Accession No. MI0016786, SEQ ID NO: 312) having a hairpin-like structure as a precursor.
- hsa-miR-4446-3p gene or “hsa-miR-4446-3p” refers to the hsa-miR-4446-3p gene described in SEQ ID NO: 78 (miRBase Accession No. MIMAT0018965) and other species homologs or orthologs. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127.
- hsa-miR-4446-3p “hsa-mir-4446” (miRBase Accession No. MI0016789, SEQ ID NO: 313) 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: 79 or other biological species. A homolog or ortholog is included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4447”, “hsa-mir-4447” (miRBase Accession No. MI0016790, SEQ ID NO: 314) 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: 80 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. Further, “hsa-miR-4448” is known as “hsa-mir-4448” (miRBase Accession No. MI0016791, SEQ ID NO: 315) having a hairpin-like structure as a precursor.
- hsa-miR-4449 gene or “hsa-miR-4449” refers to the hsa-miR-4449 gene (miRBase Accession No. MIMAT0018968) described in SEQ ID NO: 81 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4449”, “hsa-mir-4449” (miRBase Accession No. MI0016792, SEQ ID NO: 316) 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: 82 or other biological species. Homologs or orthologs are included. The gene is 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: 317) having a hairpin-like structure as a precursor is known.
- hsa-miR-4455 gene or “hsa-miR-4455” refers to the hsa-miR-4455 gene (miRBase Accession No. MIMAT0018977) described in SEQ ID NO: 83 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. Further, “hsa-miR-4455” is known as “hsa-mir-4455” (miRBase Accession No. MI0016801, SEQ ID NO: 318) having a hairpin-like structure as a precursor.
- hsa-miR-4459 gene or “hsa-miR-4459” refers to the hsa-miR-4459 gene (miRBase Accession No. MIMAT0018981) described in SEQ ID NO: 84 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4459”, “hsa-mir-4459” (miRBase Accession No. MI0016805, SEQ ID NO: 319) having a hairpin-like structure as a precursor is known.
- hsa-miR-4462 gene or “hsa-miR-4462” refers to the hsa-miR-4462 gene (miRBase Accession No. MIMAT0018986) described in SEQ ID NO: 85 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4462”, “hsa-mir-4462” (miRBase Accession No. MI0016810, SEQ ID NO: 320) having a hairpin-like structure as a precursor is known.
- hsa-miR-4466 gene or “hsa-miR-4466” refers to the hsa-miR-4466 gene (miRBase Accession No. MIMAT0018993) described in SEQ ID NO: 86 and other biological species. Homologs or orthologs are included. The gene is 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: 321) having a hairpin-like structure as a precursor is known.
- hsa-miR-4467 gene or “hsa-miR-4467” refers to the hsa-miR-4467 gene (miRBase Accession No. MIMAT0018994) described in SEQ ID NO: 87 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4467”, “hsa-mir-4467” (miRBase Accession No. MI0016818, SEQ ID NO: 322) having a hairpin-like structure as a precursor is known.
- hsa-miR-4480 gene or “hsa-miR-4480” refers to the hsa-miR-4480 gene (miRBase Accession No. MIMAT0019014) described in SEQ ID NO: 88 and other biological species. A homolog or ortholog is included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. Also, “hsa-miR-4480” is known as “hsa-mir-4480” (miRBase Accession No. MI0016841, SEQ ID NO: 323) having a hairpin-like structure as a precursor.
- hsa-miR-4483 gene or “hsa-miR-4483” refers to the hsa-miR-4483 gene (miRBase Accession No. MIMAT0019017) described in SEQ ID NO: 89 or other species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4483”, “hsa-mir-4483” (miRBase Accession No. MI0016844, SEQ ID NO: 324) 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: 90 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4484”, “hsa-mir-4484” (miRBase Accession No. MI0016845, SEQ ID NO: 325) having a hairpin-like structure as a precursor is known.
- hsa-miR-4485-5p gene or “hsa-miR-4485-5p” refers to the hsa-miR-4485-5p gene described in SEQ ID NO: 91 (miRBase Accession No. MIMAT0032116) and other species homologues or orthologues are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4485-5p”, “hsa-mir-4485” (miRBase Accession No. MI0016846, SEQ ID NO: 326) 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: 92 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127.
- “hsa-miR-4488” is known as “hsa-mir-4488” (miRBase Accession No. MI0016849, SEQ ID NO: 327) having a hairpin-like structure as a precursor.
- hsa-miR-4492 gene or “hsa-miR-4492” refers to the hsa-miR-4492 gene (miRBase Accession No. MIMAT0019027) described in SEQ ID NO: 93 or other biological species. Homologs or orthologs are included. The gene is 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: 328) having a hairpin-like structure as a precursor.
- hsa-miR-4505 gene or “hsa-miR-4505” refers to the hsa-miR-4505 gene (miRBase Accession No. MIMAT0019041) described in SEQ ID NO: 94 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4505”, “hsa-mir-4505” (miRBase Accession No. MI0016868, SEQ ID NO: 329) having a hairpin-like structure as a precursor is known.
- hsa-miR-4515 gene or “hsa-miR-4515” refers to the hsa-miR-4515 gene (miRBase Accession No. MIMAT0019052) described in SEQ ID NO: 95 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4515”, “hsa-mir-4515” (miRBase Accession No. MI0016881, SEQ ID NO: 330) having a hairpin-like structure as a precursor is known.
- hsa-miR-4525 gene or “hsa-miR-4525” refers to the hsa-miR-4525 gene (miRBase Accession No. MIMAT0019064) described in SEQ ID NO: 96 or other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4525”, “hsa-mir-4525” (miRBase Accession No. MI0016892, SEQ ID NO: 331) having a hairpin-like structure as a precursor is known.
- hsa-miR-4534 gene or “hsa-miR-4534” refers to the hsa-miR-4534 gene (miRBase Accession No. MIMAT0019073) described in SEQ ID NO: 97 or other species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127.
- hsa-miR-4534 “hsa-mir-4534” (miRBase Accession No. MI0016901, SEQ ID NO: 332) having a hairpin-like structure as a precursor is known.
- hsa-miR-4535 gene or “hsa-miR-4535” refers to the hsa-miR-4535 gene (miRBase Accession No. MIMAT0019075) described in SEQ ID NO: 98 and other biological species. Homologs or orthologs are included. The gene is described in Jim DD et al., 2010, Blood. 116, e118-e127. As for “hsa-miR-4535”, “hsa-mir-4535” (miRBase Accession No. MI0016903, SEQ ID NO: 333) having a hairpin-like structure as a precursor is known.
- hsa-miR-4633-3p gene or “hsa-miR-4633-3p” refers to the hsa-miR-4633-3p gene described in SEQ ID NO: 99 (miRBase Accession No. MIMAT0019690) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. Further, “hsa-miR-4633-3p” is known as “hsa-mir-4633” (miRBase Accession No. MI0017260, SEQ ID NO: 334), which has a hairpin-like structure as a precursor.
- hsa-miR-4634 gene or “hsa-miR-4634” refers to the hsa-miR-4634 gene (miRBase Accession No. MIMAT0019691) described in SEQ ID NO: 100 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. Also, “hsa-miR-4634” is known as “hsa-mir-4634” (miRBase Accession No. MI0017261, SEQ ID NO: 335) 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: 101 (miRBase Accession No. MIMAT0019699) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4640-5p “hsa-mir-4640” (miRBase Accession No. MI0017267, SEQ ID NO: 336) having a hairpin-like structure as a precursor is known.
- hsa-miR-4649-5p gene or “hsa-miR-4649-5p” refers to the hsa-miR-4649-5p gene described in SEQ ID NO: 102 (miRBase Accession No. MIMAT0019711) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4649-5p” “hsa-mir-4649” (miRBase Accession No. MI0017276, SEQ ID NO: 337) having a hairpin-like structure as a precursor is known.
- hsa-miR-4651 gene or “hsa-miR-4651” refers to the hsa-miR-4651 gene (miRBase Accession No. MIMAT0019715) described in SEQ ID NO: 103 or other species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. Also, “hsa-miR-4651” is known as “hsa-mir-4651” (miRBase Accession No. MI0017279, SEQ ID NO: 338) having a hairpin-like structure as a precursor.
- hsa-miR-4652-5p gene or “hsa-miR-4652-5p” refers to the hsa-miR-4652-5p gene described in SEQ ID NO: 104 (miRBase Accession No. MIMAT0019716) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4652-5p” is known as “hsa-mir-4652” (miRBase Accession No. MI0017280, SEQ ID NO: 339) having a hairpin-like structure as a precursor.
- hsa-miR-4655-5p gene or “hsa-miR-4655-5p” refers to the hsa-miR-4655-5p gene described in SEQ ID NO: 105 (miRBase Accession No. MIMAT0019721) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4655-5p”, “hsa-mir-4655” (miRBase Accession No. MI0017283, SEQ ID NO: 340) having a hairpin-like structure as a precursor is known.
- hsa-miR-4656 gene or “hsa-miR-4656” refers to the hsa-miR-4656 gene (miRBase Accession No. MIMAT0019723) described in SEQ ID NO: 106 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4656 “hsa-mir-4656” (miRBase Accession No. MI0017284, SEQ ID NO: 341) having a hairpin-like structure as a precursor is known.
- hsa-miR-4658 gene or “hsa-miR-4658” refers to the hsa-miR-4658 gene (miRBase Accession No. MIMAT0019725) described in SEQ ID NO: 107 and other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4658”, “hsa-mir-4658” (miRBase Accession No. MI0017286, SEQ ID NO: 342) having a hairpin-like structure as a precursor is known.
- hsa-miR-4663 gene or “hsa-miR-4663” refers to the hsa-miR-4663 gene (miRBase Accession No. MIMAT0019735) described in SEQ ID NO: 108 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4663”, “hsa-mir-4663” (miRBase Accession No. MI0017292, SEQ ID NO: 343) 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: 109 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4673”, “hsa-mir-4673” (miRBase Accession No. MI0017304, SEQ ID NO: 344) having a hairpin-like structure as a precursor is known.
- hsa-miR-4675 gene or “hsa-miR-4675” refers to the hsa-miR-4675 gene (miRBase Accession No. MIMAT0019757) described in SEQ ID NO: 110 and other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4675 is known as “hsa-mir-4675” (miRBase Accession No. MI0017306, SEQ ID NO: 345) having a hairpin-like structure as a precursor.
- hsa-miR-4687-3p gene or “hsa-miR-4687-3p” refers to the hsa-miR-4687-3p gene described in SEQ ID NO: 111 (miRBase Accession No. 1). MIMAT0019775) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4687-3p”, “hsa-mir-4687” (miRBase Accession No. MI0017319, SEQ ID NO: 346) having a hairpin-like structure as a precursor is known.
- hsa-miR-4687-5p gene or “hsa-miR-4687-5p” refers to the hsa-miR-4687-5p gene described in SEQ ID NO: 112 (miRBase Accession No. MIMAT0019774) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4687-5p”, “hsa-mir-4687” (miRBase Accession No. MI0017319, SEQ ID NO: 347) having a hairpin-like structure as a precursor is known.
- hsa-miR-4690-5p gene or “hsa-miR-4690-5p” refers to the hsa-miR-4690-5p gene described in SEQ ID NO: 113 (miRBase Accession No. MIMAT0019779) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4690-5p” “hsa-mir-4690” (miRBase Accession No. MI0017323, SEQ ID NO: 348) having a hairpin-like structure as a precursor is known.
- hsa-miR-4695-5p gene or “hsa-miR-4695-5p” refers to the hsa-miR-4695-5p gene described in SEQ ID NO: 114 (miRBase Accession No. MIMAT0019788) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4695-5p”, “hsa-mir-4695” (miRBase Accession No. MI0017328, SEQ ID NO: 349) having a hairpin-like structure as a precursor is known.
- hsa-miR-4697-5p gene or “hsa-miR-4697-5p” refers to the hsa-miR-4697-5p gene (miRBase Accession No. MIMAT0019791) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4697-5p “hsa-mir-4697” (miRBase Accession No. MI0017330, SEQ ID NO: 350) 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: 116 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4706”, “hsa-mir-4706” (miRBase Accession No. MI0017339, SEQ ID NO: 351) having a hairpin-like structure as a precursor is known.
- hsa-miR-4707-3p gene or “hsa-miR-4707-3p” refers to the hsa-miR-4707-3p gene described in SEQ ID NO: 117 (miRBase Accession No. MIMAT0019808) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4707-3p”, “hsa-mir-4707” (miRBase Accession No. MI0017340, SEQ ID NO: 352) having a hairpin-like structure as a precursor is known.
- 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 is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4707-5p “hsa-mir-4707” (miRBase Accession No. MI0017340, SEQ ID NO: 353) having a hairpin-like structure as a precursor is known.
- hsa-miR-4708-3p gene or “hsa-miR-4708-3p” refers to the hsa-miR-4708-3p gene described in SEQ ID NO: 119 (miRBase Accession No. MIMAT0019810) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. Also, “hsa-miR-4708-3p” is known as “hsa-mir-4708” (miRBase Accession No. MI0017341, SEQ ID NO: 354) having a hairpin-like structure as a precursor.
- hsa-miR-4710 gene or “hsa-miR-4710” refers to the hsa-miR-4710 gene (miRBase Accession No. MIMAT0019815) described in SEQ ID NO: 120 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4710 “hsa-mir-4710” (miRBase Accession No. MI0017344, SEQ ID NO: 355) having a hairpin-like structure as a precursor is known.
- hsa-miR-4718 gene or “hsa-miR-4718” refers to the hsa-miR-4718 gene (miRBase Accession No. MIMAT0019831) described in SEQ ID NO: 121 and other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4718” is known as “hsa-mir-4718” (miRBase Accession No. MI0017353, SEQ ID NO: 356) having a hairpin-like structure as a precursor.
- hsa-miR-4722-5p gene or “hsa-miR-4722-5p” refers to the hsa-miR-4722-5p gene described in SEQ ID NO: 122 (miRBase Accession No. MIMAT0019836) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4722-5p” “hsa-mir-4722” (miRBase Accession No. MI0017357, SEQ ID NO: 357) having a hairpin-like structure as a precursor is known.
- hsa-miR-4725-3p gene or “hsa-miR-4725-3p” refers to the hsa-miR-4725-3p gene described in SEQ ID NO: 123 (miRBase Accession No. MIMAT0019844) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. Also, “hsa-miR-4725-3p” is known as “hsa-mir-4725” (miRBase Accession No. MI0017362, SEQ ID NO: 358) having a hairpin-like structure as a precursor.
- hsa-miR-4726-5p gene or “hsa-miR-4726-5p” refers to the hsa-miR-4726-5p gene described in SEQ ID NO: 124 (miRBase Accession No. MIMAT0019845) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4726-5p” “hsa-mir-4726” (miRBase Accession No. MI0017363, SEQ ID NO: 359) having a hairpin-like structure as a precursor is known.
- hsa-miR-4727-3p gene or “hsa-miR-4727-3p” refers to the hsa-miR-4727-3p gene described in SEQ ID NO: 125 (miRBase Accession No. MIMAT0019848) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4727-3p” “hsa-mir-4727” (miRBase Accession No. MI0017364, SEQ ID NO: 360) 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: 126 (miRBase Accession No. MIMAT0019849) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. Also, “hsa-miR-4728-5p” is known as “hsa-mir-4728” (miRBase Accession No. MI0017365, SEQ ID NO: 361) having a hairpin-like structure as a precursor.
- hsa-miR-4731-5p gene or “hsa-miR-4731-5p” refers to the hsa-miR-4731-5p gene described in SEQ ID NO: 127 (miRBase Accession No. MIMAT0019853) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4731-5p” is known as “hsa-mir-4731” (miRBase Accession No. MI0017368, SEQ ID NO: 362) having a hairpin-like structure as a precursor.
- hsa-miR-4736 gene or “hsa-miR-4736” refers to the hsa-miR-4736 gene (miRBase Accession No. MIMAT0019862) described in SEQ ID NO: 128 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4736 “hsa-mir-4736” (miRBase Accession No. MI0017373, SEQ ID NO: 363) 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: 129 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4739”, “hsa-mir-4739” (miRBase Accession No. MI0017377, SEQ ID NO: 364) having a hairpin-like structure as a precursor is known.
- hsa-miR-4740-5p gene or “hsa-miR-4740-5p” refers to the hsa-miR-4740-5p gene (miRBase Accession No. MIMAT0019869) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4740-5p is known as “hsa-mir-4740” (miRBase Accession No. MI0017378, SEQ ID NO: 365) having a hairpin-like structure as a precursor.
- hsa-miR-4741 gene or “hsa-miR-4741” refers to the hsa-miR-4741 gene (miRBase Accession No. MIMAT0019871) described in SEQ ID NO: 131 and other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4741” is known as “hsa-mir-4741” (miRBase Accession No. MI0017379, SEQ ID NO: 366) having a hairpin-like structure as a precursor.
- hsa-miR-4750-5p gene or “hsa-miR-4750-5p” refers to the hsa-miR-4750-5p gene described in SEQ ID NO: 132 (miRBase Accession No. MIMAT0019887) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. Also, “hsa-miR-4750-5p” is known as “hsa-mir-4750” (miRBase Accession No. MI0017389, SEQ ID NO: 367) having a hairpin-like structure as a precursor.
- hsa-miR-4755-3p gene or “hsa-miR-4755-3p” refers to the hsa-miR-4755-3p gene described in SEQ ID NO: 133 (miRBase Accession No. MIMAT0019896) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. Further, “hsa-miR-4755-3p” is known as “hsa-mir-4755” (miRBase Accession No. MI0017395, SEQ ID NO: 368) having a hairpin-like structure as a precursor.
- hsa-miR-4763-3p gene or “hsa-miR-4763-3p” refers to the hsa-miR-4763-3p gene (miRBase Accession No. MIMAT0019913) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- hsa-miR-4763-3p is known as “hsa-mir-4763” (miRBase Accession No. MI0017404, SEQ ID NO: 369) having a hairpin-like structure as a precursor.
- hsa-miR-4771 gene or “hsa-miR-4771” refers to the hsa-miR-4771 gene (miRBase Accession No. MIMAT0019925) described in SEQ ID NO: 135 and other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. “Hsa-miR-4771” has “hsa-mir-4771-1” (miRBase Accession No. MI0017412, SEQ ID NO: 479) and “hsa-mir-4771-2” having a hairpin-like structure as a precursor thereof. (MiRBBase Accession No. MI0017413, SEQ ID NO: 491) is known.
- hsa-miR-4783-3p gene or “hsa-miR-4783-3p” refers to the hsa-miR-4783-3p gene described in SEQ ID NO: 136 (miRBase Accession No. MIMAT0019947) and other species homologues or orthologues are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. As for “hsa-miR-4783-3p”, “hsa-mir-4783” (miRBase Accession No. MI0017428, SEQ ID NO: 370) having a hairpin-like structure as a precursor is known.
- hsa-miR-4783-5p gene or “hsa-miR-4783-5p” refers to the hsa-miR-4783-5p gene (miRBase Accession No. 137 described in SEQ ID NO: 137). MIMAT0019946) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4783-5p” “hsa-mir-4783” (miRBase Accession No. MI0017428, SEQ ID NO: 371) having a hairpin-like structure as a precursor is known.
- hsa-miR-4787-3p gene or “hsa-miR-4787-3p” refers to the hsa-miR-4787-3p gene described in SEQ ID NO: 138 (miRBase Accession No. MIMAT0019957) and other species homologs or orthologs. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86.
- “hsa-miR-4787-3p” “hsa-mir-4787” (miRBase Accession No. MI0017434, SEQ ID NO: 372) having a hairpin-like structure as a precursor is known.
- hsa-miR-4792 gene or “hsa-miR-4792” refers to the hsa-miR-4792 gene (miRBase Accession No. MIMAT0019964) described in SEQ ID NO: 139 or other biological species. Homologs or orthologs are included. The gene is described in Persson H et al., 2011, Cancer Res. 71, 78-86. “Hsa-miR-4792” is known as “hsa-mir-4792” (miRBase Accession No. MI0017439, SEQ ID NO: 373) having a hairpin-like structure as a precursor.
- hsa-miR-498 gene or “hsa-miR-498” refers to the hsa-miR-498 gene (miRBase Accession No. MIMAT0002824) described in SEQ ID NO: 140 or other species. Homologs or orthologs are included. The gene is described in Bentwich I et al., 2005, Nat Genet. 37, 766-770. As for “hsa-miR-498”, “hsa-mir-498” (miRBase Accession No. MI0003142, SEQ ID NO: 374) having a hairpin-like structure as a precursor is known.
- hsa-miR-5008-5p gene or “hsa-miR-5008-5p” refers to the hsa-miR-5008-5p gene described in SEQ ID NO: 141 (miRBase Accession No. MIMAT0021039) and other species homologs or orthologs. The gene is described in Hansen TB et al., 2011, RNA Biol. 8, 378-383.
- hsa-miR-5008-5p “hsa-mir-5008” (miRBase Accession No. MI0017876, SEQ ID NO: 375) having a hairpin-like structure as a precursor is known.
- hsa-miR-5010-5p gene or “hsa-miR-5010-5p” refers to the hsa-miR-5010-5p gene described in SEQ ID NO: 142 (miRBase Accession No. MIMAT0021043) and other species homologs or orthologs. The gene is described in Hansen TB et al., 2011, RNA Biol. 8, 378-383. Also, “hsa-miR-5010-5p” is known as “hsa-mir-5010” (miRBase Accession No. MI0017878, SEQ ID NO: 376) having a hairpin-like structure as a precursor.
- hsa-miR-504-3p gene or “hsa-miR-504-3p” refers to the hsa-miR-504-3p gene described in SEQ ID NO: 143 (miRBase Accession No. MIMAT0026612) and other species homologues or orthologues are included. The gene is described in Bentwich I et al., 2005, Nat Genet. 37, 766-770. Further, “hsa-miR-504-3p” is known as “hsa-mir-504” (miRBase Accession No. MI0003189, SEQ ID NO: 377) having a hairpin-like structure as a precursor.
- hsa-miR-5195-3p gene or “hsa-miR-5195-3p” refers to the hsa-miR-5195-3p gene described in SEQ ID NO: 144 (miRBase Accession No. MIMAT0021127) and other species homologues or orthologues are included. The gene is described in Schotte D et al., 2011, Leukemia. 25, 1389-1399.
- hsa-miR-5195-3p “hsa-mir-5195” (miRBase Accession No. MI0018174, SEQ ID NO: 378) having a hairpin-like structure as a precursor is known.
- hsa-miR-550a-5p gene or “hsa-miR-550a-5p” refers to the hsa-miR-550a-5p gene (miRBase Accession No. MIMAT0004800) and other species homologs or orthologs. The gene is described in Cummins JM et al., 2006, Proc Natl Acad Sci US A. 103, 3687-3692. In addition, “hsa-miR-550a-5p” has “hsa-mir-550a-1” (miRBase Accession No.
- MI0003600 SEQ ID NO: 480 having a hairpin-like structure as a precursor thereof, and “hsa-mir-550a-5p”.
- -2 "(miRBBase Accession No. MI0003601, SEQ ID NO: 492) is known.
- hsa-miR-5572 gene or “hsa-miR-5572” refers to the hsa-miR-5572 gene (miRBase Accession No. MIMAT0022260) described in SEQ ID NO: 146 or other biological species. Homologs or orthologs are included. The gene is described in Tandon M. et al., 2012, Oral Dis. 18 and 127-131. As for “hsa-miR-5572”, “hsa-mir-5572” (miRBase Accession No. MI0019117, SEQ ID NO: 379) having a hairpin-like structure as a precursor is known.
- hsa-miR-5739 gene or “hsa-miR-5739” refers to the hsa-miR-5739 gene (miRBase Accession No. MIMAT0023116) described in SEQ ID NO: 147 or other biological species. Homologs or orthologs are included. Genes are described in Yoo JK et al., 2011, Biochem Biophys Res Commun. 415, 258-262. Also, “hsa-miR-5739” is known as “hsa-mir-5739” (miRBase Accession No. MI0019412, SEQ ID NO: 380), which has a hairpin-like structure as a precursor.
- hsa-miR-6075 gene or “hsa-miR-6075” refers to the hsa-miR-6075 gene (miRBase Accession No. MIMAT0023700) described in SEQ ID NO: 148 or other biological species. Homologs or orthologs are included. The gene is described in Voellenkle C et al., 2012, RNA. 18, 472-484.
- hsa-miR-6075 “hsa-mir-6075” (miRBase Accession No. MI0020352, SEQ ID NO: 381) having a hairpin-like structure as a precursor 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: 149 or other biological species. Homologs or orthologs are included. The gene is described in Voellenkle C et al., 2012, RNA. 18, 472-484.
- hsa-miR-6076 is known as “hsa-mir-6076” (miRBase Accession No. MI0020353, SEQ ID NO: 382) having a hairpin-like structure as a precursor.
- hsa-miR-6088 gene or “hsa-miR-6088” refers to the hsa-miR-6088 gene (miRBase Accession No. MIMAT0023713) described in SEQ ID NO: 150 or other biological species. A homolog or ortholog is included. The gene can be found in Yoo JK et al., 2012, Stem Cells Dev. 21, 2049-2057.
- hsa-miR-6088 “hsa-mir-6088” (miRBase Accession No. MI0020365, SEQ ID NO: 383) having a hairpin-like structure as a precursor is known.
- hsa-miR-6124 gene or “hsa-miR-6124” refers to the hsa-miR-6124 gene (miRBase Accession No. MIMAT0024597) described in SEQ ID NO: 151 or other biological species. Homologs or orthologs are included. The gene is described in Smith JL et al., 2012, J Virol. 86, 5278-5287. As for “hsa-miR-6124”, “hsa-mir-6124” (miRBase Accession No. MI0021258, SEQ ID NO: 384) 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: 152 or other biological species. Homologs or orthologs are included. The gene is disclosed in Dannemann M et al., 2012, Genome Biol Evol. 4, Volume 552-564. Also, “hsa-miR-6131” is known as “hsa-mir-6131” (miRBase Accession No. MI0021276, SEQ ID NO: 385), which has a hairpin-like structure as a precursor.
- hsa-miR-6132 gene or “hsa-miR-6132” refers to the hsa-miR-6132 gene (miRBase Accession No. MIMAT0024616) described in SEQ ID NO: 153 or other biological species. Homologs or orthologs are included. The gene is disclosed in Dannemann M et al., 2012, Genome Biol Evol. 4, Volume 552-564. As for “hsa-miR-6132”, “hsa-mir-6132” (miRBase Accession No. MI0021277, SEQ ID NO: 386) 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: 154 or other biological species. A homolog or ortholog is included. The gene is described in Cummins JM et al., 2006, Proc Natl Acad Sci US A. 103, 3687-3692.
- hsa-miR-614 is known as “hsa-mir-614” (miRBase Accession No. MI0003627, SEQ ID NO: 387) 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: 155 (miRBase Accession No. MIMAT0004804) and other species homologues or orthologues are included. The gene is described in Cummins JM et al., 2006, Proc Natl Acad Sci US A. 103, 3687-3692. Also, “hsa-miR-615-5p” is known as “hsa-mir-615” (miRBase Accession No. MI0003628, SEQ ID NO: 388) 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: 156 (miRBase Accession No. MIMAT0026622) and other species homologues or orthologues are included. The gene is described in Cummins JM et al., 2006, Proc Natl Acad Sci US A. 103, 3687-3692. As for “hsa-miR-619-5p”, “hsa-mir-619” (miRBase Accession No. MI0003633, SEQ ID NO: 389) having a hairpin-like structure as a precursor is known.
- hsa-miR-642b-3p gene or “hsa-miR-642b-3p” refers to the hsa-miR-642b-3p gene described in SEQ ID NO: 157 (miRBase Accession No. MIMAT0018444) and other species homologs or orthologs. The gene is described in Witten D et al., 2010, BMC Biol. , 8, 58.
- hsa-miR-642b-3p is known as “hsa-mir-642b” (miRBase Accession No. MI0016685, SEQ ID NO: 390) having a hairpin-like structure as a precursor.
- hsa-miR-6510-5p gene or “hsa-miR-6510-5p” refers to the hsa-miR-6510-5p gene described in SEQ ID NO: 158 (miRBase Accession No. MIMAT0025476) and other species homologs or orthologs. The gene is described in Joyce CE et al., 2011, Hum Mol Genet. 20, Vol. 4025-4040.
- hsa-miR-6510-5p is known as “hsa-mir-6510” (miRBase Accession No. MI0022222, SEQ ID NO: 391) having a hairpin-like structure as a precursor.
- hsa-miR-6511a-5p gene or “hsa-miR-6511a-5p” refers to the hsa-miR-6511a-5p gene described in SEQ ID NO: 159 (miRBase Accession No. MIMAT0025478) and other species homologs or orthologs. The gene is described in Joyce CE et al., 2011, Hum Mol Genet. 20, Vol. 4025-4040. “Hsa-miR-6511a-5p” has a hairpin-like structure as a precursor thereof, “hsa-mir-6651a-1” (miRBase Accession No.
- -2 "(miRBase Accession No. MI0023564, SEQ ID NO: 501),” hsa-mir-6651a-3 "(miRBase Accession No. MI0023565, SEQ ID NO: 503), and” hsa-mir-6651a-4 "(miRBaseAccion No. MI0023566, SEQ ID NO: 505) is known.
- hsa-miR-6515-3p gene or “hsa-miR-6515-3p” refers to the hsa-miR-6515-3p gene described in SEQ ID NO: 160 (miRBase Accession No. MIMAT0025487) and other species homologs or orthologs. The gene is described in Joyce CE et al., 2011, Hum Mol Genet. 20, Vol. 4025-4040.
- hsa-miR-6515-3p is known as “hsa-mir-6515” (miRBase Accession No. MI0022227, SEQ ID NO: 392) having a hairpin-like structure as a precursor.
- hsa-miR-6515-5p gene or “hsa-miR-6515-5p” refers to the hsa-miR-6515-5p gene described in SEQ ID NO: 161 (miRBase Accession No. MIMAT0025486) and other species homologues or orthologues are included. The gene is described in Joyce CE et al., 2011, Hum Mol Genet. 20, Vol. 4025-4040. As for “hsa-miR-6515-5p”, “hsa-mir-6515” (miRBase Accession No. MI0022227, SEQ ID NO: 393) having a hairpin-like structure as a precursor is known.
- hsa-miR-663b gene or “hsa-miR-663b” refers to the hsa-miR-663b gene (miRBase Accession No. MIMAT0005867) described in SEQ ID NO: 162 and other biological species. Homologs or orthologs are included. The gene is described in Takada S et al., 2008, Leukemia. , Vol.22, 1274-1278. In addition, “hsa-miR-663b” is known as “hsa-mir-663b” (miRBase Accession No. MI0006336, SEQ ID NO: 394) having a hairpin-like structure as a precursor.
- hsa-miR-6716-5p gene or “hsa-miR-6716-5p” refers to the hsa-miR-6716-5p gene described in SEQ ID NO: 163 (miRBase Accession No. MIMAT0025844) and other species homologs or orthologs. The gene is described in Li Y et al., 2012, Gene. 497, 330-335. Also, “hsa-miR-6716-5p” is known as “hsa-mir-6716” (miRBase Accession No. MI0022550, SEQ ID NO: 395), which has 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 described in SEQ ID NO: 164 (miRBase Accession No. MIMAT0025846) and other species homologues or orthologues are included. The gene is described in Li Y et al., 2012, Gene. 497, 330-335. “Hsa-miR-6717-5p” is known as “hsa-mir-6717” (miRBase Accession No. MI0022551, SEQ ID NO: 396) having a hairpin-like structure as a precursor.
- hsa-miR-6722-3p gene or “hsa-miR-6722-3p” refers to the hsa-miR-6722-3p gene described in SEQ ID NO: 165 (miRBase Accession No. MIMAT0025854) and other species homologs or orthologs are included. The gene is described in Li Y et al., 2012, Gene. 497, 330-335. As for “hsa-miR-6722-3p”, “hsa-mir-6722” (miRBase Accession No. MI0022557, SEQ ID NO: 397) having a hairpin-like structure as a precursor is known.
- hsa-miR-6724-5p gene or “hsa-miR-6724-5p” refers to the hsa-miR-6724-5p gene described in SEQ ID NO: 166 (miRBase Accession No. MIMAT0025856) and other species homologs or orthologs. The gene is described in Li Y et al., 2012, Gene. 497, 330-335. “Hsa-miR-6724-5p” has a hairpin-like structure as its precursor, “hsa-mir-6724-1” (miRBase Accession No. MI0022559, SEQ ID NO: 500), and “hsa-mir-6724”.
- hsa-miR-6726-5p gene or “hsa-miR-6726-5p” refers to the hsa-miR-6726-5p gene described in SEQ ID NO: 167 (miRBase Accession No. MIMAT0027353) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. In addition, “hsa-miR-6726-5p” is known as “hsa-mir-6726” (miRBase Accession No. MI0022571, SEQ ID NO: 398) having a hairpin-like structure as a precursor.
- hsa-miR-6737-5p gene or “hsa-miR-6737-5p” refers to the hsa-miR-6737-5p gene (miRBase Accession No. MIMAT0027375) and other species homologues or orthologues are included.
- the gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645.
- hsa-miR-6737-5p “hsa-mir-6737” (miRBase Accession No. MI0022582, SEQ ID NO: 399) having a hairpin-like structure as a precursor is known.
- hsa-miR-6741-5p gene or “hsa-miR-6741-5p” refers to the hsa-miR-6741-5p gene described in SEQ ID NO: 169 (miRBase Accession No. MIMAT0027383) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6741-5p”, “hsa-mir-6741” (miRBase Accession No. MI0022586, SEQ ID NO: 400) having a hairpin-like structure as a precursor is known.
- hsa-miR-6742-5p gene or “hsa-miR-6742-5p” refers to the hsa-miR-6742-5p gene described in SEQ ID NO: 170 (miRBase Accession No. MIMAT0027385) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6742-5p”, “hsa-mir-6742” (miRBase Accession No. MI0022587, SEQ ID NO: 401) having a hairpin-like structure as a precursor is known.
- hsa-miR-6743-5p gene or “hsa-miR-6743-5p” refers to the hsa-miR-6743-5p gene described in SEQ ID NO: 171 (miRBase Accession No. MIMAT0027387) and other species homologs or orthologs are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6743-5p”, “hsa-mir-6743” (miRBase Accession No. MI0022588, SEQ ID NO: 402) 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: 172 (miRBase Accession No. MIMAT0027392) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6746-5p”, “hsa-mir-6746” (miRBase Accession No. MI0022591, SEQ ID NO: 403) 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: 173 (miRBase Accession No. MIMAT0027398) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6749-5p”, “hsa-mir-6749” (miRBase Accession No. MI0022594, SEQ ID NO: 404) having a hairpin-like structure as a precursor is known.
- hsa-miR-6760-5p gene or “hsa-miR-6760-5p” refers to the hsa-miR-6760-5p gene described in SEQ ID NO: 174 (miRBase Accession No. MIMAT0027420) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Also, “hsa-miR-6760-5p” is known as “hsa-mir-6760” (miRBase Accession No. MI0022605, SEQ ID NO: 405) having a hairpin-like structure as a precursor.
- hsa-miR-6762-5p gene or “hsa-miR-6762-5p” refers to the hsa-miR-6762-5p gene described in SEQ ID NO: 175 (miRBase Accession No. MIMAT0027424) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-6762-5p” is known as “hsa-mir-6762” (miRBase Accession No. MI0022607, SEQ ID NO: 406) 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: 176 (miRBase Accession No. MIMAT0027431) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6765-3p”, “hsa-mir-6765” (miRBase Accession No. MI0022610, SEQ ID NO: 407) 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: 177 (miRBase Accession No. MIMAT0027430) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6765-5p”, “hsa-mir-6765” (miRBase Accession No. MI0022610, SEQ ID NO: 408) having a hairpin-like structure as a precursor is known.
- hsa-miR-6766-3p gene or “hsa-miR-6766-3p” refers to the hsa-miR-6766-3p gene described in SEQ ID NO: 178 (miRBase Accession No. MIMAT0027433) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6766-3p”, “hsa-mir-6766” (miRBase Accession No. MI0022611, SEQ ID NO: 409) having a hairpin-like structure as a precursor is known.
- hsa-miR-6766-5p gene or “hsa-miR-6766-5p” refers to the hsa-miR-6766-5p gene described in SEQ ID NO: 179 (miRBase Accession No. MIMAT0027432) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6766-5p”, “hsa-mir-6766” (miRBase Accession No. MI0022611, SEQ ID NO: 410) having a hairpin-like structure as a precursor is known.
- hsa-miR-6671-5p gene or “hsa-miR-6771-5p” refers to the hsa-miR-6671-5p gene described in SEQ ID NO: 180 (miRBase Accession No. MIMAT0027442) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-6771-5p” is known as “hsa-mir-6711” (miRBase Accession No. MI0022616, SEQ ID NO: 411) having a hairpin-like structure as a precursor.
- hsa-miR-6774-5p gene or “hsa-miR-6774-5p” refers to the hsa-miR-6774-5p gene described in SEQ ID NO: 181 (miRBase Accession No. MIMAT0027448) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6774-5p”, “hsa-mir-6774” (miRBase Accession No. MI0022619, SEQ ID NO: 412) 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: 182 (miRBase Accession No. MIMAT0027454) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6777-5p”, “hsa-mir-6777” (miRBase Accession No. MI0022622, SEQ ID NO: 413) having a hairpin-like structure as a precursor is known.
- hsa-miR-6778-5p gene or “hsa-miR-6778-5p” refers to the hsa-miR-6778-5p gene described in SEQ ID NO: 183 (miRBase Accession No. MIMAT0027456) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645.
- hsa-miR-6778-5p is known as “hsa-mir-6778” (miRBase Accession No. MI0022623, SEQ ID NO: 414) 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: 184 (miRBase Accession No. 1). MIMAT0027572) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6780b-5p”, “hsa-mir-6780b” (miRBase Accession No. MI0022681, SEQ ID NO: 415) 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: 185 (miRBase Accession No. MIMAT0027462) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-6781-5p” is known as “hsa-mir-6781” (miRBase Accession No. MI0022626, SEQ ID NO: 416) having a hairpin-like structure as a precursor.
- hsa-miR-6782-5p gene or “hsa-miR-6782-5p” refers to the hsa-miR-6782-5p gene described in SEQ ID NO: 186 (miRBase Accession No. MIMAT0027464) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. “Hsa-miR-6782-5p” is known as “hsa-mir-6782” (miRBase Accession No. MI0022627, SEQ ID NO: 417) having a hairpin-like structure as a precursor.
- hsa-miR-6784-5p gene or “hsa-miR-6784-5p” refers to the hsa-miR-6784-5p gene described in SEQ ID NO: 187 (miRBase Accession No. MIMAT0027468) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. In addition, “hsa-miR-6784-5p” is known as “hsa-mir-6784” (miRBase Accession No. MI0022629, SEQ ID NO: 418), which has 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 described in SEQ ID NO: 188 (miRBase Accession No. MIMAT0027470) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6785-5p”, “hsa-mir-6785” (miRBase Accession No. MI0022630, SEQ ID NO: 419) 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 described in SEQ ID NO: 189 (miRBase Accession No. MIMAT0027474) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6787-5p”, “hsa-mir-6787” (miRBase Accession No. MI0022632, SEQ ID NO: 420) 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: 190 (miRBase Accession No. MIMAT0027478) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6789-5p”, “hsa-mir-6789” (miRBase Accession No. MI0022634, SEQ ID NO: 421) 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: 191 (miRBase Accession No. MIMAT0027482) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. In addition, “hsa-miR-6791-5p” is known as “hsa-mir-6791” (miRBase Accession No. MI0022636, SEQ ID NO: 422) having a hairpin-like structure as a precursor.
- hsa-miR-6794-5p gene or “hsa-miR-6794-5p” refers to the hsa-miR-6794-5p gene described in SEQ ID NO: 192 (miRBase Accession No. MIMAT0027488) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6794-5p”, “hsa-mir-6794” (miRBase Accession No. MI0022639, SEQ ID NO: 423) having a hairpin-like structure as a precursor is known.
- hsa-miR-6800-5p gene or “hsa-miR-6800-5p” refers to the hsa-miR-6800-5p gene described in SEQ ID NO: 193 (miRBase Accession No. MIMAT0027500) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6800-5p”, “hsa-mir-6800” (miRBase Accession No. MI0022645, SEQ ID NO: 424) having a hairpin-like structure as a precursor is known.
- hsa-miR-6802-5p gene or “hsa-miR-6802-5p” refers to the hsa-miR-6802-5p gene described in SEQ ID NO: 194 (miRBase Accession No. MIMAT0027504) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6802-5p”, “hsa-mir-6802” (miRBase Accession No. MI0022647, SEQ ID NO: 425) having a hairpin-like structure as a precursor is known.
- hsa-miR-6803-5p gene or “hsa-miR-6803-5p” refer to the hsa-miR-6803-5p gene described in SEQ ID NO: 195 (miRBase Accession No. MIMAT0027506) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645.
- hsa-miR-6803-5p is known as “hsa-mir-6803” (miRBase Accession No. MI0022648, SEQ ID NO: 426) having a hairpin-like structure as a precursor.
- hsa-miR-6812-5p gene or “hsa-miR-6812-5p” refers to the hsa-miR-6812-5p gene described in SEQ ID NO: 196 (miRBase Accession No. MIMAT0027524) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6812-5p”, “hsa-mir-6812” (miRBase Accession No. MI0022657, SEQ ID NO: 427) 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: 197 (miRBase Accession No. MIMAT0027532) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6816-5p”, “hsa-mir-6816” (miRBase Accession No. MI0022661, SEQ ID NO: 428) having a hairpin-like structure as a precursor is known.
- hsa-miR-6819-5p gene or “hsa-miR-6819-5p” refers to the hsa-miR-6819-5p gene described in SEQ ID NO: 198 (miRBase Accession No. MIMAT0027538) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645.
- hsa-miR-6819-5p is known as “hsa-mir-6819” (miRBase Accession No. MI0022664, SEQ ID NO: 429) 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: 199 (miRBase Accession No. MIMAT0027542) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Also, “hsa-miR-6821-5p” is known as “hsa-mir-6821” (miRBase Accession No. MI0022666, SEQ ID NO: 430) 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: 200 (miRBase Accession No. MIMAT0027552) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6826-5p”, “hsa-mir-6826” (miRBase Accession No. MI0022671, SEQ ID NO: 431) having a hairpin-like structure as a precursor is known.
- hsa-miR-6831-5p gene or “hsa-miR-6831-5p” refers to the hsa-miR-6831-5p gene described in SEQ ID NO: 201 (miRBase Accession No. MIMAT0027562) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-6831-5p” is known as “hsa-mir-6831” (miRBase Accession No. MI0022676, SEQ ID NO: 432) having a hairpin-like structure as a precursor.
- hsa-miR-6836-3p gene or “hsa-miR-6836-3p” refers to the hsa-miR-683-3p gene (miRBase Accession No. MIMAT0027575) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645.
- hsa-miR-6836-3p “hsa-mir-6836” (miRBase Accession No. MI0022682, SEQ ID NO: 433) having a hairpin-like structure as a precursor is known.
- hsa-miR-6840-3p gene or “hsa-miR-6840-3p” refers to the hsa-miR-6840-3p gene (miRBase Accession No. MIMAT0027583) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645.
- hsa-miR-6840-3p is known as “hsa-mir-6840” (miRBase Accession No. MI0022686, SEQ ID NO: 434) having a hairpin-like structure as a precursor.
- hsa-miR-6842-5p gene or “hsa-miR-6842-5p” refers to the hsa-miR-6842-5p gene described in SEQ ID NO: 204 (miRBase Accession No. MIMAT0027586) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6842-5p”, “hsa-mir-6842” (miRBase Accession No. MI0022688, SEQ ID NO: 435) having a hairpin-like structure as a precursor is known.
- hsa-miR-6850-5p gene or “hsa-miR-6850-5p” refers to the hsa-miR-6850-5p gene described in SEQ ID NO: 205 (miRBase Accession No. MIMAT0027600) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Also, “hsa-miR-6850-5p” is known as “hsa-mir-6850” (miRBase Accession No. MI0022696, SEQ ID NO: 436) having a hairpin-like structure as a precursor.
- hsa-miR-6861-5p gene or “hsa-miR-6861-5p” refers to the hsa-miR-6861-5p gene described in SEQ ID NO: 206 (miRBase Accession No. MIMAT0027623) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-6861-5p” is known as “hsa-mir-6861” (miRBase Accession No. MI0022708, SEQ ID NO: 437) having 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: 207 (miRBase Accession No. MIMAT0027638) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6869-5p”, “hsa-mir-6869” (miRBase Accession No. MI0022716, SEQ ID NO: 438) having a hairpin-like structure as a precursor is known.
- hsa-miR-6870-5p gene or “hsa-miR-6870-5p” refers to the hsa-miR-6870-5p gene described in SEQ ID NO: 208 (miRBase Accession No. MIMAT0027640) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Also, “hsa-miR-6870-5p” is known as “hsa-mir-6870” (miRBase Accession No. MI0022717, SEQ ID NO: 439) having a hairpin-like structure as a precursor.
- hsa-miR-6877-5p gene or “hsa-miR-6877-5p” refers to the hsa-miR-6877-5p gene (miRBase Accession No. MIMAT0027654) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Also, “hsa-miR-6877-5p” is known as “hsa-mir-6877” (miRBase Accession No. MI0022724, SEQ ID NO: 440) having a hairpin-like structure as a precursor.
- hsa-miR-6879-5p gene or “hsa-miR-6879-5p” refers to the hsa-miR-6879-5p gene described in SEQ ID NO: 210 (miRBase Accession No. MIMAT0027658) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6879-5p”, “hsa-mir-6879” (miRBase Accession No. MI0022726, SEQ ID NO: 441) having a hairpin-like structure as a precursor is known.
- hsa-miR-6880-3p gene or “hsa-miR-6880-3p” refers to the hsa-miR-6880-3p gene described in SEQ ID NO: 211 (miRBase Accession No. MIMAT0027661) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-6880-3p”, “hsa-mir-6880” (miRBase Accession No. MI0022727, SEQ ID NO: 442) 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: 212 (miRBase Accession No. MIMAT0027660) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-6880-5p” is known as “hsa-mir-6880” (miRBase Accession No. MI0022727, SEQ ID NO: 443) having a hairpin-like structure as a precursor.
- hsa-miR-6885-5p gene or “hsa-miR-6885-5p” refers to the hsa-miR-6885-5p gene described in SEQ ID NO: 213 (miRBase Accession No. MIMAT0027670) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Also, “hsa-miR-6885-5p” is known as “hsa-mir-6885” (miRBase Accession No. MI0022732, SEQ ID NO: 444) having a hairpin-like structure as a precursor.
- hsa-miR-687-5p gene or “hsa-miR-6887-5p” refers to the hsa-miR-6687-5p gene (miRBase Accession No. MIMAT0027674) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645.
- hsa-miR-687-5p is known as “hsa-mir-6687” (miRBase Accession No. MI0022734, SEQ ID NO: 445) 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 described in SEQ ID NO: 215 (miRBase Accession No. MIMAT0028111) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-7107-5p” is known as “hsa-mir-7107” (miRBase Accession No. MI0022958, SEQ ID NO: 446) having a hairpin-like structure as a precursor.
- hsa-miR-7108-3p gene or “hsa-miR-7108-3p” refers to the hsa-miR-7108-3p gene described in SEQ ID NO: 216 (miRBase Accession No. MIMAT0028114) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-7108-3p” is known as “hsa-mir-7108” (miRBase Accession No. MI0022959, SEQ ID NO: 447) 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: 217 (miRBase Accession No. MIMAT0028115) and other species homologs or orthologs. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. Further, “hsa-miR-7109-5p” is known as “hsa-mir-7109” (miRBase Accession No. MI0022960, SEQ ID NO: 448) having a hairpin-like structure as a precursor.
- hsa-miR-711 gene or “hsa-miR-711” refers to the hsa-miR-711 gene (miRBase Accession No. MIMAT0012734) described in SEQ ID NO: 218 or other biological species. Homologs or orthologs are included. The gene is described in Artzi S et al., 2008, BMC Bioinformatics. , 9, 39.
- hsa-miR-711 is known as “hsa-mir-711” (miRBase Accession No. MI0012488, SEQ ID NO: 449) 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: 219 (miRBase Accession No. MIMAT0028124) and other species homologues or orthologues are included. The gene is described in Ladewig E et al., 2012, Genome Res. , Vol. 22, 1634-1645. As for “hsa-miR-7113-3p”, “hsa-mir-7113” (miRBase Accession No. MI0022964, SEQ ID NO: 450) having a hairpin-like structure as a precursor is known.
- hsa-miR-7150 gene or “hsa-miR-7150” refers to the hsa-miR-7150 gene (miRBase Accession No. MIMAT0028211) described in SEQ ID NO: 220 or other species. Homologs or orthologs are included. The gene is described in Oulas A et al., 2009, Nucleic Acids Res. 37, 3276-3287. Also, “hsa-miR-7150” is known as “hsa-mir-7150” (miRBase Accession No. MI0023610, SEQ ID NO: 451) 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: 221 (miRBase Accession No. MIMAT0004945) and other species homologs or orthologs. The gene is described in Berezikov E et al., 2006, Genome Res. 16, pp. 1299-1298. Also, “hsa-miR-744-5p” is known as “hsa-mir-744” (miRBase Accession No. MI0005559, SEQ ID NO: 452) having a hairpin-like structure as a precursor.
- hsa-miR-7975 gene or “hsa-miR-7975” refers to the hsa-miR-7975 gene (miRBase Accession No. MIMAT0031178) described in SEQ ID NO: 222 or other biological species. Homologs or orthologs are included. The gene is described in Velthut-Meikas A et al., 2013, Endocrinol. 27, 1128-1141. As for “hsa-miR-7975”, “hsa-mir-7975” (miRBase Accession No. MI0025751, SEQ ID NO: 453), which has 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: 223 or other biological species. Homologs or orthologs are included. The gene is described in Velthut-Meikas A et al., 2013, Endocrinol. 27, 1128-1141. As for “hsa-miR-7777”, “hsa-mir-7777” (miRBase Accession No. MI0025753, SEQ ID NO: 454) having a hairpin-like structure as a precursor is known.
- hsa-miR-8052 gene or “hsa-miR-8052” refers to the hsa-miR-8052 gene (miRBase Accession No. MIMAT0030979) described in SEQ ID NO: 224 or other biological species. Homologs or orthologs are included. The gene is described in Wang HJ et al., 2013, Shock. 39, 480-487. As for “hsa-miR-8052”, “hsa-mir-8052” (miRBase Accession No. MI0025888, SEQ ID NO: 455) 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: 225 or other biological species. Homologs or orthologs are included. The gene is described in Wang HJ et al., 2013, Shock. , 39, 480-487. “Hsa-miR-8069” has a hairpin-like structure as a precursor thereof, “hsa-mir-8069-1” (miRBase Accession No. MI0025905, SEQ ID NO: 481), and “hsa-mir-8069-2” (MiRBBase Accession No. MI0031519, SEQ ID NO: 493) is known.
- hsa-miR-8073 gene or “hsa-miR-8073” refers to the hsa-miR-8073 gene (miRBase Accession No. MIMAT0031000) described in SEQ ID NO: 226 or other biological species. Homologs or orthologs are included. The gene is described in Wang HJ et al., 2013, Shock. 39, 480-487. As for “hsa-miR-8073”, “hsa-mir-8073” (miRBase Accession No. MI0025909, SEQ ID NO: 456) having a hairpin-like structure as a precursor is known.
- hsa-miR-887-3p gene or “hsa-miR-887-3p” refers to the hsa-miR-887-3p gene described in SEQ ID NO: 227 (miRBase Accession No. MIMAT0004951) and other species homologs or orthologs. The gene is described in Berezikov E et al., 2006, Genome Res. 16, pp. 1299-1298.
- hsa-miR-887-3p “hsa-mir-887” (miRBase Accession No. MI0005562, SEQ ID NO: 457) having a hairpin-like structure as a precursor is known.
- hsa-miR-937-5p gene or “hsa-miR-937-5p” refers to the hsa-miR-937-5p gene described in SEQ ID NO: 228 (miRBase Accession No. MIMAT0022938) and other species homologs or orthologs. The gene is described in Lui WO et al., 2007, Cancer Res. 67, 6031-6043.
- hsa-miR-937-5p “hsa-mir-937” (miRBase Accession No. MI0005759, SEQ ID NO: 458) having a hairpin-like structure as a precursor is known.
- hsa-miR-1202 gene or “hsa-miR-1202” refers to the hsa-miR- 1202 gene (miRBase Accession No. MIMAT0005865) described in SEQ ID NO: 229 or other biological species. Homologs or orthologs are included. The gene is described in Martin S et al., 2008, Leukemia. , Vol. 22, 330-338. Also, “hsa-miR-1202” is known as “hsa-mir-1220” (miRBase Accession No. MI0006334, SEQ ID NO: 459), which has a hairpin-like structure as a precursor.
- hsa-miR-1207-5p gene or “hsa-miR-1207-5p” refers to the hsa-miR-1207-5p gene described in SEQ ID NO: 230 (miRBase Accession No. MIMAT0005871) and other species homologues or orthologues are included. The gene is described in Huppi K et al., 2008, Mol Cancer Res. 6, Vol. 212-221.
- hsa-miR-1207-5p “hsa-mir-1207” (miRBase Accession No. MI0006340, SEQ ID NO: 460) having a hairpin-like structure as a precursor is known.
- hsa-miR-1246 gene or “hsa-miR-1246” refers to the hsa-miR-1246 gene (miRBase Accession No. MIMAT0005898) described in SEQ ID NO: 231 or other biological species. Homologs or orthologs are included. The gene is described in Morin RD et al., 2008, Genome Res. 18, 610-621.
- hsa-miR-1246 is known as “hsa-mir-1246” (miRBase Accession No. MI0006381, SEQ ID NO: 461) having a hairpin-like structure as a precursor.
- hsa-miR-1254 gene or “hsa-miR-1254” refers to the hsa-miR-1254 gene (miRBase Accession No. MIMAT0005905) described in SEQ ID NO: 232 or other biological species. Homologs or orthologs are included. The gene is described in Morin RD et al., 2008, Genome Res. 18, 610-621. “Hsa-miR-1254” has a hairpin-like structure as its precursor, “hsa-mir-1254-1” (miRBase Accession No. MI0006388, SEQ ID NO: 482), and “hsa-mir-12254-2” (MiRBBase Accession No. MI0016747, SEQ ID NO: 494) is known.
- hsa-miR-135a-3p gene or “hsa-miR-135a-3p” refers to the hsa-miR-135a-3p gene described in SEQ ID NO: 233 (miRBase Accession No. MIMAT0004595) and other species homologs or orthologs. The gene is described in Lagos-Quintana M et al., 2002, Curr Biol. 12, Vol. 735-739.
- “hsa-miR-135a-3p” is known as “hsa-mir-135a-1” (miRBase Accession No. MI000052, SEQ ID NO: 462) having a hairpin-like structure as a precursor.
- hsa-miR-1469 gene or “hsa-miR-1469” refers to the hsa-miR-1469 gene (miRBase Accession No. MIMAT0007347) described in SEQ ID NO: 234 or other biological species. Homologs or orthologs are included. The gene is described in Kawaji H et al., 2008, BMC Genomics. , Vol. 9, 157. As for “hsa-miR-1469”, “hsa-mir-1469” (miRBase Accession No. MI00000074, SEQ ID NO: 463) having a hairpin-like structure as a precursor is known.
- hsa-miR-149-3p gene or “hsa-miR-149-3p” refer to the hsa-miR-149-3p gene described in SEQ ID NO: 235 (miRBase Accession No. MIMAT0004609) and other species homologues or orthologues are included. The gene is described in Lagos-Quintana M et al., 2002, Curr Biol. 12, Vol. 735-739. Also, “hsa-miR-149-3p” is known as “hsa-mir-149” (miRBase Accession No. MI0000478, SEQ ID NO: 464) having a hairpin-like structure as a precursor.
- hsa-miR-150-3p gene or “hsa-miR-150-3p” refer to the hsa-miR-150-3p gene described in SEQ ID NO: 236 (miRBase Accession No. MIMAT0004610) and other species homologues or orthologues are included. The gene is described in Lagos-Quintana M et al., 2002, Curr Biol. 12, Vol. 735-739. As for “hsa-miR-150-3p”, “hsa-mir-150” (miRBase Accession No. MI0000479, SEQ ID NO: 465) 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 described in SEQ ID NO: 237 (miRBase Accession No. MIMAT0007890) and other species homologs or orthologs. The gene is described in Bar M et al., 2008, Stem Cells. 26, 2496-2505.
- hsa-miR-1914-3p is known as “hsa-mir-1914” (miRBase Accession No. MI0008335, SEQ ID NO: 466) having a hairpin-like structure as a precursor.
- hsa-miR-191-5p gene or “hsa-miR-191-5p” refers to the hsa-miR-191-5p gene described in SEQ ID NO: 238 (miRBase Accession No. MIMAT000040) and other species homologues or orthologues are included. The gene is described in Lagos-Quintana M et al., 2003, RNA. 9, 175-179. Further, “hsa-miR-191-5p” is known as “hsa-mir-191” (miRBase Accession No. MI000065, SEQ ID NO: 467) having a hairpin-like structure as a precursor.
- hsa-miR-423-5p gene or “hsa-miR-423-5p” refers to the hsa-miR-423-5p gene described in SEQ ID NO: 239 (miRBase Accession No. MIMAT0004748) and other species homologs or orthologs. The gene is described in Kasshima K et al., 2004, Biochem Biophys Res Commun. 322, 403-410. As for “hsa-miR-423-5p”, “hsa-mir-423” (miRBase Accession No. MI0001445, SEQ ID NO: 468) 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: 240 or other species. Homologs or orthologs are included. The gene is described in Cummins JM et al., 2006, Proc Natl Acad Sci US A. 103, 3687-3692.
- hsa-miR-663a is known as “hsa-mir-663a” (miRBase Accession No. MI0003672, SEQ ID NO: 469) 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 described in SEQ ID NO: 241. Genes (miRBase Accession No. MIMAT0004508) and other species homologues or orthologues are included. The gene is described in Mouretos Z et al., 2002, Genes Dev. 16, 720-728. In addition, “hsa-miR-92a-2-5p” is known as “hsa-mir-92a-2” (miRBase Accession No. MI00000094, SEQ ID NO: 470) having a hairpin-like structure as a precursor.
- hsa-miR-92a-3p gene or “hsa-miR-92a-3p” refers to the hsa-miR-92a-3p gene described in SEQ ID NO: 242 (miRBase Accession No. MIMAT00000092) and other species homologs or orthologs. The gene is described in Mouretos Z et al., 2002, Genes Dev. 16, 720-728. “Hsa-miR-92a-3p” has a hairpin-like structure as a precursor thereof, “hsa-mir-92a-1” (miRBase Accession No. MI00000093, SEQ ID NO: 483), and “hsa-mir-92a”. -2 "(miRBBase Accession No. MI00000094, SEQ ID NO: 495) is known.
- hsa-miR-940 gene or “hsa-miR-940” refers to the hsa-miR-940 gene (miRBase Accession No. MIMAT0004983) described in SEQ ID NO: 243 or other biological species. Homologs or orthologs are included. The gene is described in Lui WO et al., 2007, Cancer Res. 67, 6031-6043.
- hsa-miR-940 is known as “hsa-mir-940” (miRBase Accession No. MI0005762, SEQ ID NO: 471) having a hairpin-like structure as a precursor.
- isomiR miRNA RD. Et al., 2008, Genome Res., Vol. 18, p.610-621.
- miRBBase Release 21 in addition to the nucleotide sequence represented by any of SEQ ID NOs: 1 to 243, a number of variants and fragments of the nucleotide sequence represented by any of SEQ ID NOs: 507 to 766 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 243. That is, SEQ ID NOs: 1, 2, 3, 8, 9, 10, 12, 13, 14, 15, 16, 17, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30 of the present invention.
- SEQ ID NOs: 1, 2, 3, 4, 8, 9, 10, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 24, 25, 26, 27, 28 of the present invention 29, 30, 31, 32, 33, 34, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 53, 54, 55, 56, 58 61, 62, 63, 67, 68, 71, 72, 73, 74, 75, 77, 78, 80, 81, 82, 84, 86, 90, 91, 92, 93, 95, 96, 101, 105 107, 109, 111, 112, 113, 114, 116, 117, 118, 119, 120, 122, 123, 124, 125, 126, 127, 129, 131, 132, 133, 134, 135, 136, 138 139, 142, 14 145, 146, 150, 151, 152, 154, 155, 156, 157,
- polynucleotide having a sequence represented by ⁇ 766 a polynucleotide having a sequence represented by ⁇ 766.
- polynucleotides that are numerous isomiRs of SEQ ID NOs: 1 to 243 registered in miRBase can be mentioned.
- examples of the polynucleotide containing the base sequence represented by any one of SEQ ID NOs: 1 to 243 include the polynucleotides represented by any one of SEQ ID NOs: 507 to 766, which are precursors.
- 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.
- bladder cancer can be detected easily and with high accuracy. For example, using a measurement value of the expression level of one to several miRNAs in a patient's blood, serum and / or plasma that can be collected minimally invasively, it is easy to detect whether the patient has bladder cancer or not. Can do.
- FIG. 2 shows a discrimination score plot of the learning sample group (A) and the verification sample group (B) based on one miRNA discriminant.
- FIG. 3 shows a discrimination score-specific plot of the verification sample group based on the discriminant of one miRNA.
- FIGS. 4A and 4B show discrimination score plots of verification sample groups by stage (A) and by in-wall progress (B) according to one miRNA discriminant.
- FIGS. 4C to 4D show discrimination score plots of a group of verification specimens classified by histological atypia (C) and first / relapsed (D) by one miRNA discriminant.
- FIG. 5 shows a discrimination score plot of the learning sample group (A) and the verification sample group (B) by the discriminant of three miRNAs.
- FIG. 6 shows a discrimination score-specific plot of the verification sample group based on the discriminant of three miRNAs.
- FIGS. 7A and 7B show discrimination score plots of verification sample groups by stage (A) and by in-wall progress (B) according to the discriminant of three miRNAs.
- FIG. 7C-D shows a discrimination score plot of the verification sample group according to histological atypia (C) and initial / relapse (D) according to the discriminant of three miRNAs.
- FIG. 8 shows a discrimination score plot of the learning sample group (A) and the verification sample group (B) based on the discriminant of four miRNAs.
- FIG. 9 shows a discrimination score-specific plot of the verification sample group based on the discriminant of four miRNAs.
- FIG. 10A-B shows a discrimination score plot of the verification specimen group for each stage (A) and for each in-wall advancement degree (B) according to the discriminant of four miRNAs.
- FIG. 10C-D shows a discrimination score plot of the verification specimen group according to histological atypia (C) and initial / relapse (D) according to the discriminant of four miRNAs.
- FIG. 11 shows a discrimination score plot of the learning sample group (A) and the verification sample group (B) based on the discriminant of five miRNAs.
- FIG. 12 shows a discrimination score-specific plot of the verification sample group based on the discriminant of five miRNAs.
- FIGS. 13A and 13B show discrimination score plots of the verification specimen group for each stage (A) and for each in-wall progress (B) according to the discriminant of five miRNAs.
- FIG. 13C-D shows a discrimination score plot of the verification specimen group according to histological atypia (C) and initial / relapse (D) according to the discriminant of 5 miRNAs.
- FIG. 14 shows a disease type discrimination score plot of a verification sample group based on a discriminant of three miRNAs.
- FIGS. 15A and 15B show discrimination score plots of verification sample groups by stage (A) and by in-wall progress (B) by the discriminant of three miRNAs.
- FIG. 15C-D shows a discrimination score plot of the verification sample group according to histological atypia (C) and initial / recurrence (D) according to the discriminant of three miRNAs.
- FIGS. 16 shows a discrimination score-specific plot of the verification sample group based on the discriminant of 10 miRNAs.
- FIGS. 17A and 17B show discrimination score plots of verification sample groups by stage (A) and by in-wall progress (B) according to the discriminant of 10 miRNAs.
- FIGS. 17C-D show the discrimination score plots of the histological atypical grade (C) and initial / recurrent (D) verification sample groups according to the discriminant of 10 miRNAs.
- FIG. 18 shows a discrimination score-specific plot of the verification specimen group based on 104 discriminants of miRNA.
- FIGS. 19A and 19B show discrimination score plots of the verification specimen group for each stage (A) and for each in-wall progress (B) according to the discriminant of 104 miRNAs.
- FIGS. 19C-D show the discrimination score plots of the histological atypical grade (C) and initial / recurrent (D) verification sample groups according to the 104 miRNA discriminants.
- FIG. 20 shows the ROC curves of the learning sample group (A) and the verification sample group (C) for one miRNA, and the ROC curves of the learning sample group (B) and the verification sample group (D) in the combination of seven miRNAs.
- FIG. 21 shows a disease type discrimination score plot in a combination of 7 miRNAs.
- Bladder cancer target nucleic acid A bladder for detecting the presence and / or absence of bladder cancer or bladder cancer cells using the nucleic acid probe or primer for bladder cancer detection as defined above of the present invention.
- Major target nucleic acids as cancer markers include miR-6087, miR-1185-1-3p, miR-1185-2-3p, miR-1193, miR-1199-5p, miR-1225-5p, miR-1227 -5p, miR-1228-3p, miR-1228-5p, miR-1237-5p, miR-1238-5p, miR-1247-3p, miR-1268a, miR-1268b, miR-1273g-3p, miR-128 -2-5p, miR-1343-3p, miR-1343-5p, miR-1470, miR-17-3p, miR -187-5p, miR-1908-3p, miR-1908-5p, miR-1909-3p, miR-1915-3p, miR-210-5p, miR-24-3p
- miR-1202 miR-1207-5p, miR-1246, miR-1254, miR-135a-3p, miR-1469, miR-149- 3p, miR-150-3p, miR-1914-3p, miR-191-5p, miR-423-5p, miR-663a, miR-92a-2-5p, miR-92a-3p, miR-940
- miRNAs can also be preferably used as the target nucleic acid.
- the miRNA includes, for example, human genes containing the nucleotide sequence represented by any of SEQ ID NOs: 1 to 243 (ie, miR-6087, miR-1185-1-3p, miR-1185-2-3p, respectively) , MiR-1193, miR-1199-5p, miR-1225-5p, miR-1227-5p, miR-1228-3p, miR-1228-5p, miR-1237-5p, miR-1238-5p, miR-1247 -3p, miR-1268a, miR-1268b, miR-1273g-3p, miR-128-2-5p, miR-1343-3p, miR-1343-5p, miR-1470, miR-17-3p, miR-187 -5p, miR-1908-3p, miR-1908-5p, miR-1909- p, miR-1915-3p, miR-210-5p, miR-24-3p, miR-2467-3p, miR-2861, miR-296-3p, miR-29b-3p
- a preferred target nucleic acid is a human gene comprising the base sequence represented by any of SEQ ID NOs: 1 to 243, a transcription product thereof, more preferably the transcription product, ie, miRNA, its precursor RNA, pri-miRNA or pre- miRNA.
- the first target gene is the hsa-miR-6087 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the second target gene is the hsa-miR-1185-1-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the third target gene is the hsa-miR-1185-2-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the fourth target gene is the hsa-miR-1193 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the fifth target gene is the hsa-miR-1199-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the sixth target gene is the hsa-miR-1225-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the seventh target gene is the hsa-miR-1227-5p gene, their homologues, their transcription products, or their mutants or derivatives.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the eighth target gene is the hsa-miR-1228-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the ninth target gene is the hsa-miR-1228-5p gene, their homologues, their transcripts, or their mutants or derivatives. Until now, there is no known report that a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the tenth target gene is the hsa-miR-1237-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the eleventh target gene is the hsa-miR-1238-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the twelfth target gene is the hsa-miR-1247-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the thirteenth target gene is the hsa-miR-1268a gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the fourteenth target gene is the hsa-miR-1268b gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the fifteenth target gene is the hsa-miR-1273g-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the sixteenth target gene is the hsa-miR-128-2-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 17th target gene is the hsa-miR-1343-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 18th target gene is the hsa-miR-1343-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the nineteenth target gene is the hsa-miR-1470 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the twentieth target gene is an hsa-miR-17-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 21st target gene is an hsa-miR-187-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 22nd target gene is the hsa-miR-1908-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 23rd target gene is the hsa-miR-1908-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 24th target gene is the hsa-miR-1909-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 25th target gene is the hsa-miR-1915-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 26th target gene is an hsa-miR-210-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 27th target gene is the hsa-miR-24-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 28th target gene is the hsa-miR-2467-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 29th target gene is the hsa-miR-2861 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 30th target gene is the hsa-miR-296-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the thirty-first target gene is the hsa-miR-29b-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the thirty-second target gene is the hsa-miR-3131 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 33rd target gene is the hsa-miR-3154 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 34th target gene is the hsa-miR-3158-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 35th target gene is an hsa-miR-3160-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 36th target gene is the hsa-miR-3162-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 37th target gene is the hsa-miR-3178 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 38th target gene is the hsa-miR-3180-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 39th target gene is the hsa-miR-3184-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 40th target gene is the hsa-miR-3185 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 41st target gene is the hsa-miR-3194-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the forty-second target gene is the hsa-miR-3195 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 43rd target gene is the hsa-miR-3197 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 44th target gene is an hsa-miR-320a gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 45th target gene is the hsa-miR-320b gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 46th target gene is the hsa-miR-328-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 47th target gene is the hsa-miR-342-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 48th target gene is the hsa-miR-345-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 49th target gene is the hsa-miR-3616-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 50th target gene is the hsa-miR-3619-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 51st target gene is the hsa-miR-3620-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 52nd target gene is the hsa-miR-3621 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 53rd target gene is the hsa-miR-3622a-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 54th target gene is the hsa-miR-3648 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 55th target gene is the hsa-miR-3652 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 56th target gene is the hsa-miR-3656 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 57th target gene is the hsa-miR-3663-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 58th target gene is the hsa-miR-3679-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 59th target gene is the hsa-miR-371b-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 60th target gene is the hsa-miR-373-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 61st target gene is the hsa-miR-3913 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 62nd target gene is the hsa-miR-3940-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 63rd target gene is the hsa-miR-3960 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 64th target gene is the hsa-miR-4258 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 65th target gene is the hsa-miR-4259 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 66th target gene is the hsa-miR-4270 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 67th target gene is the hsa-miR-4286 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 68th target gene is the hsa-miR-4298 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 69th target gene is the hsa-miR-4322 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 70th target gene is the hsa-miR-4327 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 71st target gene is the hsa-miR-4417 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 72nd target gene is the hsa-miR-4419b gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 73rd target gene is the hsa-miR-4429 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 74th target gene is the hsa-miR-4430 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 75th target gene is the hsa-miR-4433a-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 76th target gene is the hsa-miR-4436b-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 77th target gene is the hsa-miR-4443 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 78th target gene is the hsa-miR-4446-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 79th target gene is the hsa-miR-4447 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 80th target gene is the hsa-miR-4448 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 81st target gene is the hsa-miR-4449 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 82nd target gene is the hsa-miR-4454 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 83rd target gene is the hsa-miR-4455 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 84th target gene is the hsa-miR-4459 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 85th target gene is the hsa-miR-4462 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 86th target gene is the hsa-miR-4466 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 87th target gene is the hsa-miR-4467 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 88th target gene is the hsa-miR-4480 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 89th target gene is the hsa-miR-4483 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 90th target gene is the hsa-miR-4484 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 91st target gene is the hsa-miR-4485-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 92nd target gene is the hsa-miR-4488 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 93rd target gene is the hsa-miR-4492 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 94th target gene is the hsa-miR-4505 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 95th target gene is the hsa-miR-4515 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 96th target gene is the hsa-miR-4525 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 97th target gene is the hsa-miR-4534 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 98th target gene is the hsa-miR-4535 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 99th target gene is the hsa-miR-4633-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 100th target gene is the hsa-miR-4634 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 101st target gene is the hsa-miR-4640-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 102nd target gene is the hsa-miR-4649-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 103rd target gene is the hsa-miR-4651 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 104th target gene is the hsa-miR-4652-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 105th target gene is the hsa-miR-4655-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 106th target gene is the hsa-miR-4656 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 107th target gene is the hsa-miR-4658 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 108th target gene is the hsa-miR-4663 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 109th target gene is the hsa-miR-4673 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 110th target gene is the hsa-miR-4675 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 111th target gene is the hsa-miR-4687-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 112th target gene is the hsa-miR-4687-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 113th target gene is the hsa-miR-4690-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 114th target gene is the hsa-miR-4695-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 115th target gene is the hsa-miR-4697-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 116th target gene is the hsa-miR-4706 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 117th target gene is the hsa-miR-4707-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 118th target gene is the hsa-miR-4707-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 119th target gene is the hsa-miR-4708-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 120th target gene is the hsa-miR-4710 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 121st target gene is the hsa-miR-4718 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 122nd target gene is the hsa-miR-4722-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 123rd target gene is the hsa-miR-4725-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 124th target gene is the hsa-miR-4726-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 125th target gene is the hsa-miR-4727-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 126th target gene is the hsa-miR-4728-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 127th target gene is the hsa-miR-4731-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 128th target gene is the hsa-miR-4736 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 129th target gene is the hsa-miR-4739 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 130th target gene is the hsa-miR-4740-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 131st target gene is the hsa-miR-4741 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 132nd target gene is the hsa-miR-4750-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 133rd target gene is the hsa-miR-4755-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 134th target gene is the hsa-miR-4763-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 135th target gene is the hsa-miR-4771 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 136th target gene is the hsa-miR-4783-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 137th target gene is the hsa-miR-4783-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 138th target gene is the hsa-miR-4787-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 139th target gene is the hsa-miR-4792 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 140th target gene is an hsa-miR-498 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 141st target gene is the hsa-miR-5008-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 142nd target gene is the hsa-miR-5010-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 143rd target gene is the hsa-miR-504-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 144th target gene is the hsa-miR-5195-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 145th target gene is the hsa-miR-550a-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 146th target gene is the hsa-miR-5572 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 147th target gene is the hsa-miR-5739 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 148th target gene is the hsa-miR-6075 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 149th target gene is the hsa-miR-6076 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 150th target gene is the hsa-miR-6088 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 151st target gene is the hsa-miR-6124 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 152th target gene is the hsa-miR-6131 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 153rd target gene is the hsa-miR-6132 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 154th target gene is the hsa-miR-614 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 155th target gene is an hsa-miR-615-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 156th target gene is the hsa-miR-619-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 157th target gene is an hsa-miR-642b-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 158th target gene is the hsa-miR-6510-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 159th target gene is the hsa-miR-6511a-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 160th target gene is the hsa-miR-6515-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 161st target gene is the hsa-miR-6515-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 162nd target gene is the hsa-miR-663b gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 163rd target gene is the hsa-miR-6716-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 164th target gene is the hsa-miR-6717-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 165th target gene is the hsa-miR-6722-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 166th target gene is the hsa-miR-6724-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 167th target gene is the hsa-miR-6726-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 168th target gene is the hsa-miR-6737-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 169th target gene is the hsa-miR-6741-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 170th target gene is the hsa-miR-6742-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 171st target gene is the hsa-miR-6743-5p gene, their homologues, their transcripts, or their mutants or derivatives.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 172nd target gene is the hsa-miR-6746-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 173rd target gene is the hsa-miR-6749-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 174th target gene is the hsa-miR-6760-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 175th target gene is the hsa-miR-6762-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 176th target gene is the hsa-miR-6765-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 177th target gene is the hsa-miR-6765-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 178th target gene is the hsa-miR-6766-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 179th target gene is the hsa-miR-6766-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 180th target gene is the hsa-miR-6671-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the target gene 181 is the hsa-miR-6774-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 182nd target gene is the hsa-miR-6777-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 183rd target gene is the hsa-miR-6778-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 184th target gene is the hsa-miR-6780b-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 185th target gene is the hsa-miR-6781-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 186th target gene is the hsa-miR-6782-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 187th target gene is the hsa-miR-6784-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 188th target gene is the hsa-miR-6785-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 189th target gene is the hsa-miR-6787-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 190th target gene is the hsa-miR-6789-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 191st target gene is the hsa-miR-6791-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 192nd target gene is the hsa-miR-6794-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 193rd target gene is the hsa-miR-6800-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 194th target gene is the hsa-miR-6802-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 195th target gene is the hsa-miR-6803-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 196th target gene is the hsa-miR-6812-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 197th target gene is the hsa-miR-6816-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 198th target gene is the hsa-miR-6819-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 199th target gene is the hsa-miR-6821-5p gene, their homologues, their transcripts, or their mutants or derivatives.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 200th target gene is the hsa-miR-6826-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 201st target gene is an hsa-miR-6831-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 202nd target gene is the hsa-miR-6836-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 203rd target gene is the hsa-miR-6840-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 204th target gene is the hsa-miR-6842-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 205th target gene is the hsa-miR-6850-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 206th target gene is the hsa-miR-6861-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 207th target gene is the hsa-miR-6869-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 208th target gene is the hsa-miR-6870-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 209th target gene is the hsa-miR-6877-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 210th target gene is the hsa-miR-6879-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 211st target gene is the hsa-miR-6880-3p gene, their homologues, their transcripts, or their mutants or derivatives.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 212th target gene is the hsa-miR-6880-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 213rd target gene is the hsa-miR-6885-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 214th target gene is the hsa-miR-6687-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 215th target gene is the hsa-miR-7107-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 216th target gene is the hsa-miR-7108-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 217th target gene is the hsa-miR-7109-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 218th target gene is the hsa-miR-711 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 219th target gene is the hsa-miR-7113-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 220th target gene is the hsa-miR-7150 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the target gene 221 is the hsa-miR-744-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 222nd target gene is the hsa-miR-7975 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 223rd target gene is the hsa-miR-7777 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 224th target gene is the hsa-miR-8052 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 225th target gene is the hsa-miR-8069 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 226th target gene is the hsa-miR-8073 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 227th target gene is the hsa-miR-887-3p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 228th target gene is the hsa-miR-937-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- a change in the expression of a gene or a transcript thereof can be a marker for bladder cancer.
- the 229th target gene is the miR-1220 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 be a marker for bladder cancer Patent Document 1.
- the 230th target gene is a miR-1207-5p 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 be a marker for bladder cancer Patent Document 1.
- the target gene 231 is the miR-1246 gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- Patent Document 2 There has been known a report that changes in the expression of a gene or a transcription product thereof can serve as a bladder cancer marker.
- the 232nd target gene is a miR-1254 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 bladder cancer marker Patent Document 2.
- the target gene 233 is a miR-135a-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 be a marker for bladder cancer Patent Document 1.
- the 234th target gene is the 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 be a marker for bladder cancer Patent Document 1.
- the 235th target gene is a miR-149-3p 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 be a marker for bladder cancer Patent Document 1.
- the 236th target gene is a 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 be a marker for bladder cancer Patent Document 1.
- the 237th target gene is a miR-1914-3p 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 be a marker for bladder cancer Patent Document 1.
- the 238th target gene is a miR-191-5p 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 bladder cancer (Non-patent Document 2).
- the 239th target gene is a miR-423-5p gene, a homologue thereof, a transcription product thereof, or a mutant or derivative thereof.
- the 240th target gene is a 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 be a marker for bladder cancer Patent Document 1.
- the target gene 241 is a 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 be a marker for bladder cancer Patent Document 1.
- the 242nd target gene is a miR-92a-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 bladder cancer marker Patent Document 2.
- the target gene 243 is a miR-940 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 bladder cancer (Non-patent Document 2).
- the present invention relates to a marker for detecting bladder cancer or diagnosing bladder cancer, comprising at least one of the above target nucleic acids.
- the present invention relates to the use of at least one of the above target nucleic acids for detecting bladder cancer or for diagnosing bladder cancer.
- nucleic acid probe or primer for detection of bladder cancer In the present invention, a nucleic acid probe or primer that can be used for detecting bladder cancer or diagnosing bladder cancer is used as a target nucleic acid for bladder cancer.
- the above target nucleic acids are expressed in different amounts depending on the type of the target nucleic acid in subjects suffering from bladder cancer compared to healthy subjects, benign disease patients and subjects suffering from cancer other than bladder cancer. Some may increase or some may decrease (hereinafter referred to as “increase / decrease”). Therefore, the kit or device of the present invention provides the above target for body fluids derived from subjects suspected of suffering from bladder cancer (eg, humans) and body fluids derived from healthy subjects, benign disease patients, and cancer patients other than bladder cancer. Nucleic acid expression levels can be measured and compared, and can be used effectively to detect bladder cancer.
- the nucleic acid probe or primer that can be used in the present invention is a polynucleotide consisting of the base sequence represented by at least one of SEQ ID NOs: 1 to 228, or a nucleic acid probe that can specifically bind to the complementary strand of the polynucleotide, or A primer for amplifying a polynucleotide comprising the base sequence represented by at least one of SEQ ID NOs: 1-228.
- the nucleic acid probe or primer that can be used in the present invention further includes a polynucleotide consisting of the base sequence represented by at least one of SEQ ID NOS: 229 to 243, or a nucleic acid probe that can specifically bind to a complementary strand of the polynucleotide, Alternatively, a primer for amplifying a polynucleotide comprising the base sequence represented by at least one of SEQ ID NOs: 229 to 243 can be included.
- the nucleic acid probe or primer includes a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 766 or a polynucleotide group comprising a nucleotide sequence in which u is t in the nucleotide sequence;
- the complementary polynucleotide group, the polynucleotide group that hybridizes with DNA comprising a base sequence complementary to the base sequence under stringent conditions (described later), the complementary polynucleotide group, and the polynucleotide group It includes a combination of one or a plurality of polynucleotides selected from the group of polynucleotides containing 15 or more, preferably 17 or more consecutive bases in the base sequence.
- These polynucleotides can be used as nucleic acid probes and primers for detecting the bladder cancer marker, which is a target nucleic acid.
- nucleic acid probes or primers that can be used in the present invention are one or a plurality of polynucleotides selected from the group consisting of any of the following polynucleotides (a) to (e).
- A a polynucleotide comprising the nucleotide sequence represented by any one of SEQ ID NOs: 1 to 228 or a nucleotide sequence in which u is t in the nucleotide sequence, a variant thereof, or a derivative thereof, comprising 15 or more consecutive bases Its fragments, (B) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1-228, (C) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence complementary to the base sequence in which u is t in the base sequence, variants thereof, derivatives thereof, or 15 or more A fragment thereof containing a continuous base of (D) a polynucleotide comprising a base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence complementary to a base sequence in which u is t in the base sequence, and (E) a polynucle
- the nucleic acid probe or primer that can be used in the present invention further includes the following (f) to (j) in addition to at least one polynucleotide selected from any of the above-mentioned polynucleotides (a) to (e): Any of the polynucleotides shown can be included.
- 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 are described in, for example, Ausubel et al., Current Protocols in Molecular Biology, John Willy & Sons, US (1993); Sambrook et al., Molecular Cloning A Laboratory United, United States. Technology can be used.
- 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 nucleic acid probe and primer sequences for detecting the polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 243 are not present in vivo as miRNA or a precursor thereof.
- the base sequences represented by SEQ ID NO: 9 and SEQ ID NO: 8 are generated from the precursor represented by SEQ ID NO: 251, and this precursor has a hairpin-like structure as shown in FIG.
- the base sequences represented by SEQ ID NO: 9 and SEQ ID NO: 8 have mismatch sequences with each other. For this reason, a completely complementary base sequence to the base sequence represented by SEQ ID NO: 9 or SEQ ID NO: 8 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 243 can have an artificial base sequence that does not exist in the living body.
- Bladder cancer detection kit or device The present invention also provides a polynucleotide that can be used as a nucleic acid probe or primer in the present invention for measuring a target nucleic acid that is a bladder cancer marker (including mutants, fragments, Or a derivative), or a bladder cancer detection kit or device.
- a target nucleic acid that is a bladder cancer marker (including mutants, fragments, Or a derivative), or a bladder cancer detection kit or device.
- the target nucleic acid that is a bladder cancer marker in the present invention is preferably selected from the following group A.
- Group A miR-6087, miR-1185-1-3p, miR-1185-2-3p, miR-1193, miR-1199-5p, miR-1225-5p, miR-1227-5p, miR-1228-3p, miR- 1228-5p, miR-1237-5p, miR-1238-5p, miR-1247-3p, miR-1268a, miR-1268b, miR-1273g-3p, miR-128-2-5p, miR-1343-3p, miR-1343-5p, miR-1470, miR-17-3p, miR-187-5p, miR-1908-3p, miR-1908-5p, miR-1909-3p, miR-1915-3p, miR-210- 5p, miR-24-3p, miR-2467-3p, miR-2861, m R-296-3p, miR-29b-3p, miR-3131, miR-3154
- the additional target nucleic acid that can optionally be used for the measurement is preferably selected from group B below.
- Group B miR-1202, miR-1207-5p, miR-1246, miR-1254, miR-135a-3p, miR-1469, miR-149-3p, miR-150-3p, miR-1914-3p, miR-191- 5p, miR-423-5p, miR-663a, miR-92a-2-5p, miR-92a-3p, miR-940.
- the kit or device of the present invention is a nucleic acid that can specifically bind to a target nucleic acid that is the bladder cancer marker, preferably one or a plurality of polynucleotides selected from the polynucleotides described in 2 above or Including variants.
- the kit or device of the present invention includes a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 228 or a polynucleotide comprising (or consisting of) a nucleotide sequence in which u is t in the nucleotide sequence, A polynucleotide comprising (or consisting of) its complementary sequence, a polynucleotide that hybridizes with these polynucleotides under stringent conditions, or a variant or fragment comprising 15 or more consecutive bases of these polynucleotide sequences Can be included.
- the kit or device of the present invention further includes a nucleotide sequence represented by any one of SEQ ID NOS: 229 to 243, a polynucleotide comprising (or consisting of) a nucleotide sequence in which u is t in the nucleotide sequence, and a complementary sequence thereof
- a polynucleotide comprising (or consisting of) a polynucleotide that hybridizes with these polynucleotides under stringent conditions, or a variant or fragment comprising 15 or more consecutive bases of the polynucleotide sequence
- a variant or fragment comprising 15 or more consecutive bases of the polynucleotide sequence
- the fragment that can be included in the kit or device of the present invention is, for example, one or more, preferably two or more polynucleotides selected from the group consisting of the following (1) and (2): (1) Sequence A polynucleotide comprising 15 or more consecutive bases in a base sequence represented by any one of Nos. 1 to 228, wherein u is t, or a complementary sequence thereof. (2) A polynucleotide comprising 15 or more consecutive bases in the base sequence represented by any one of SEQ ID NOS: 229 to 243, wherein u is t, or a complementary sequence thereof.
- the polynucleotide comprises a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 228 or a polynucleotide comprising a nucleotide sequence in which u is t in the nucleotide sequence, a polynucleotide comprising a complementary sequence thereof, Polynucleotides that hybridize with these polynucleotides under stringent conditions, or variants containing 15 or more, preferably 17 or more, more preferably 19 or more consecutive bases.
- the polynucleotide is a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 229 to 243, a nucleotide sequence wherein u is t in the nucleotide sequence, or a polynucleotide comprising a complementary sequence thereof. Nucleotides, polynucleotides that hybridize with these polynucleotides under stringent conditions, or variants containing 15 or more, preferably 17 or more, more preferably 19 or more consecutive bases.
- the fragment may be a polynucleotide comprising 15 or more, preferably 17 or more, more preferably 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 polynucleotide as the target nucleic acid in the kit or device of the present invention is one or two of the polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 243 shown in Table 1 above, although the combination of 3, 4, 5, 6, 7, 8, 9, 10 or more can be mentioned, these are merely examples, and other various All possible combinations are intended to be encompassed by the present invention.
- a kit or device for discriminating a bladder cancer patient from a subject who does not suffer from bladder cancer such as a healthy person, a benign bone and soft tissue tumor and a benign disease patient, and a cancer patient other than bladder cancer
- Examples of the combination of target nucleic acids in 2 include combinations of two or more of the above-mentioned polynucleotides consisting of the base sequences represented by SEQ ID NOs shown in Table 1. Specifically, any two or more of the above polynucleotides consisting of the nucleotide sequences represented by SEQ ID NOs: 1 to 243 may be combined.
- At least one polynucleotide having a base sequence represented by SEQ ID NOs: 1 to 228 newly found it is preferable to select at least one polynucleotide having a base sequence represented by SEQ ID NOs: 1 to 228 newly found.
- a combination comprising at least one polynucleotide selected from the group consisting of the polynucleotides described in Tables 20 to 22, and more preferably from the group consisting of the polynucleotides described in Table 23 is more preferable.
- the kit or device of the present invention includes, in addition to the polynucleotide of the present invention described above (which may include a variant, a fragment or a derivative), a known polynucleotide that enables detection of bladder cancer. Nucleotides or polynucleotides that may be found in the future can also be included.
- the kit or device of the present invention includes known bladders such as the NMP22 test for detecting the nuclear matrix protein NuMA and the BTAtrak test for detecting a specific basement membrane fragment complex in addition to the above-described polynucleotide of the present invention.
- An antibody for measuring a marker for cancer testing 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, the 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, most preferably at least 5 to all polynucleotides of the above-described group A bladder cancer marker, Or a nucleic acid capable of specifically binding to each of the complementary strands of the polynucleotide.
- the kit or device of the present invention may further optionally optionally contain at least one, preferably at least 2, more preferably at least 3, most preferably at least 5 to all of the group B bladder cancer markers described above. Or a nucleic acid capable of specifically binding to each of the complementary strands of the polynucleotide.
- the kit or device of the present invention can be used for detection of bladder cancer described in 4 below.
- the present invention further relates to miR-6087, miR-1185-1-3p, miR-1185-2-3p, miR-1193, miR-1199-5p, miR-1225-5p, miR-1227-5p, miR-1228-3p, miR-1228-5p, miR-1237-5p, miR-1238-5p, miR-1247-3p, miR-1268a, miR-1268b, miR-1273g-3p, miR-128-2-5p, miR-1343-3p, miR-1343-5p, miR-1470, miR-17-3p, miR-187-5p, miR-1908-3p, miR-1908-5p, miR- 1909-3p, miR-1915-3p, miR-210-5p, miR-24-3p, m iR-2467-3p, miR-2861, miR-296-3p, miR-29b-3p, miR-3131, miR-3154, miR-3158-5p, miR-3160-5p, miR-6087, miR-11
- the expression level of the gene in the sample If the expression level of the target nucleic acid in the sample is different using the control expression level of the subject not suffering from bladder cancer (for example, comparing both expression levels), the subject Can be assessed as having cancer.
- the above-described method of the present invention enables early diagnosis of bladder cancer in a minimally invasive manner with high sensitivity and specificity, thereby providing early treatment and prognosis improvement. Enables monitoring of the effectiveness of therapeutic, radiotherapeutic, and chemotherapeutic treatments.
- RNA extraction reagent in 3D-Gene (registered trademark) RNA extraction reagent liquid sample kit (Toray Industries, Inc.)
- a general acidic phenol method Acid Guanidinium-Phenol-Chloroform (AGPC) method
- Trizol registered trademark
- an RNA extraction reagent containing acidic phenol such as Trizol (life technologies) or Isogen (Nippon Gene) may be added to prepare.
- 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 for in vitro detection of an expression product of a miRNA gene derived from bladder cancer in a specimen derived from a subject.
- the method for carrying out the method of the present invention is not limited. It can be carried out using the kit or device of the present invention described in the above (including the above-mentioned nucleic acid usable in the present invention). In this method, the kit or device is used as described above, which contains a single polynucleotide 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 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 gene expression level is determined by a quantitative technique such as Northern blot method, Southern blot method, in situ hybridization method, Northern hybridization method, Southern hybridization method, or quantitative RT-PCR method.
- a known method for specifically detecting a specific gene such as an amplification technique and a method using a next-generation sequencer, can be performed according to a conventional 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 prepared based on the RNA may be used.
- the method of the present invention is useful for diagnosis of bladder cancer or detection of the presence or absence of disease.
- the detection of bladder cancer of the present invention is included in, for example, a kit or device of the present invention using a specimen such as blood, serum, plasma, urine, etc. from a subject suspected of having bladder cancer. It can be performed by detecting in vitro the expression level of the gene detected by the nucleic acid probe or primer.
- polynucleotides consisting of more than one base sequence is statistically compared to their expression level in specimens such as blood, serum, plasma, urine, etc. of subjects not suffering from bladder cancer If it is significantly higher, the subject can be assessed as having bladder cancer.
- a specimen derived from a subject does not contain bladder cancer or a method for detecting the presence of bladder cancer is obtained by collecting a body fluid such as blood, serum, plasma, or urine of a subject. Then, the expression level of the target gene (or target nucleic acid) contained therein is determined using one or a plurality of polynucleotides (including mutants, fragments or derivatives) selected from the polynucleotide group of the present invention. By measuring, it includes evaluating the presence or absence of bladder cancer or detecting bladder cancer.
- the bladder cancer detection method of the present invention is a known or developed bladder cancer-related therapeutic agent (eg, gemcitabine as a non-limiting example) for the purpose of treating or improving the disease in, for example, bladder cancer patients.
- a known or developed bladder cancer-related therapeutic agent eg, gemcitabine as a non-limiting example
- Platinum preparations cisplatin / carboplatin
- paclitaxel methotrexate
- vinblastine adriamycin
- cisplatin paclitaxel
- taxanes docetaxel
- isofamide other platinum preparations (nedaplatin), combinations thereof, etc.) It can also be used to evaluate or diagnose the presence or absence of improvement of the disease or the degree of improvement.
- 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 of 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), evaluating the presence or absence of bladder cancer (cells) in the subject, Can be included.
- the present invention provides miR-6087, miR-1185-1-3p, miR-1185-2-3p, miR-1193, miR-1199-5p, miR-1225-5p, miR-1227-5p. , MiR-1228-3p, miR-1228-5p, miR-1237-5p, miR-1238-5p, miR-1247-3p, miR-1268a, miR-1268b, miR-1273g-3p, miR-128-2 -5p, miR-1343-3p, miR-1343-5p, miR-1470, miR-17-3p, miR-187-5p, miR-1908-3p, miR-1908-5p, miR-1909-3p, miR -1915-3p, miR-210-5p, miR-24-3p, miR-24 7-3p, miR-2861, miR-296-3p, miR-29b-3p, miR-3131, miR-3154, miR-3158-5p, miR-3160-5p, miR-3162-5p,
- evaluation is evaluation support based on the result of an in vitro examination that is not judged by a doctor.
- miR-6087 is hsa-miR-6087
- miR-1185-1-3p is hsa-miR-1185-1-3p
- miR-1185 -2-p is hsa-miR-1185-2-3p
- miR-1193 is hsa-miR-1193
- miR-1199-5p is hsa-miR-1199-5p
- miR-1225-5p Is hsa-miR-1225-5p
- miR-1227-5p is hsa-miR-1227-5p
- miR-1228-3p is hsa-miR-1228-3p
- miR-1228-5p is hsa MiR-1228-5p
- miR-1237-5p is hsa-miR-1237-5p
- miR 1238-5p is hsa-miR-1238-5p
- miR-1247-3p is hsa-miR-1247-3p
- miR-1247-3p
- miR-685-5p is hsa-miR-685-5p
- miR-6887-5p is hsa-miR-6687-5p
- miR-7107-5p is hsa-miR-7107- 5R
- miR-7108-3p is hsa-miR-7108-3p
- miR-7109-5p is hsa-miR-7109-5p
- miR-711 is hsa-miR-711
- miR- 7113-3p is hsa-miR-7113-3p
- miR-7150 is hsa-miR-7150
- miR-744-5p is hsa-miR-744-5p
- miR-7975 is hsa-miR- 7975
- miR-7777 is hsa-miR-7777
- miR-8052 is hs MiR-8052
- miR-8069 is hsa-miR-80
- the nucleic acid (specifically, probe or primer) in the method of the present invention is a polynucleotide shown in any of the following (a) to (e): (A) including a polynucleotide consisting of the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence in which u is t in the base sequence, a variant thereof, a derivative thereof, or 15 or more consecutive bases Its fragments, (B) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1-228, (C) a polynucleotide comprising the base sequence represented by any of SEQ ID NOs: 1 to 228 or a base sequence complementary to the base sequence in which u is t in the base sequence, variants thereof, derivatives thereof, or 15 or more A fragment thereof containing a continuous base of (D) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID
- miR-1220 is hsa-miR-1202
- miR-1207-5p is hsa-miR-1207-5p
- miR-1246 is hsa-miR-1246
- miR-1254 is hsa.
- MiR-1254 miR-135a-3p is hsa-miR-135a-3p
- miR-1469 is hsa-miR-1469
- miR-149-3p is hsa-miR-149-3p
- MiR-150-3p is hsa-miR-150-3p
- miR-1914-3p is hsa-miR-1914-3p
- miR-191-5p is hsa-miR-191-5p
- miR -423-5p is hsa-miR-423-5p and miR-663a is hsa-miR- MiR-92a-2-5p is hsa-miR-92a-2-5p
- miR-92a-3p is hsa-miR-92a-3p
- miR-940 is hsa-miR-940. is there.
- the expression level of the polynucleotide is measured using a nucleic acid that can specifically bind to the polynucleotide or a complementary strand of the polynucleotide, and the nucleic acid has the following (f) to (j The polynucleotide shown in any of the following: (F) a polynucleotide comprising the nucleotide sequence represented by any of SEQ ID NOs: 229 to 243 or a nucleotide sequence in which u is t in the nucleotide sequence, a variant thereof, a derivative thereof, or 15 or more consecutive bases Its fragments, (G) a polynucleotide comprising the base sequence represented by any of SEQ ID NOS: 229 to 243, (H) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOS: 229 to 243 or a nucleotide sequence complementary to a nucle
- specimens prepared from a body tissue of a subject preferably bladder tissue or renal pelvis, ureter tissue
- body fluid such as blood, serum, plasma, urine and the like.
- a biological tissue or the like extracted by surgery from which a specimen for measurement can be prepared.
- a subject refers to mammals such as, but not limited to, humans, monkeys, mice, rats, and the like, preferably humans.
- the steps can be changed according to the type of specimen used as a measurement target.
- a bladder cancer (cell) detection method is, for example, the following steps (a), (b), and (c):
- (B) RNA derived from a specimen bound to the polynucleotide or cDNA synthesized from the RNA is measured by hybridization using the polynucleotide as a nucleic acid probe or by quantitative RT-PCR using the polynucleotide as a primer.
- Step to do (C) a step of evaluating the presence or absence of bladder cancer (or a gene derived from bladder
- hybridization methods for example, Northern blot method, Southern blot method, DNA chip analysis method, in situ hybridization method, Northern hybridization method, Southern hybridization method and the like can be used. Further, a PCR method such as quantitative RT-PCR or a next generation sequencing method can be used in combination with or as an alternative to the hybridization method.
- the presence or absence of each gene expression in RNA and the expression level thereof can be detected and measured.
- radioisotope nucleic acid probe complementary strand
- 32 P, 33 P, 35 S , etc. labeled with a, fluorescent substances, subjects which it was transferred, etc.
- the signal derived from the formed DNA / RNA double-stranded label is detected with a radiation detector (BAS-1800II (Fuji Film Co., Ltd.)) , Etc.) or a method of detecting and measuring with a fluorescence detector (STORM 865 (GE Healthcare) can be exemplified).
- RNA derived from a living tissue of a subject is recovered, polyadenylated at the 3 ′ end, cDNA is prepared from the polyadenylated RNA according to a conventional method, and the target gene marker region can be amplified using this as a template.
- a pair of primers consisting of a positive strand and a reverse strand that bind to the cDNA that can be included in the detection kit or device of the present invention were hybridized with cDNA, and PCR was performed by a conventional method.
- a method for detecting single-stranded or double-stranded DNA can be exemplified.
- a method for detecting single-stranded or double-stranded DNA a method in which the PCR is performed using a primer previously labeled with a radioisotope or a fluorescent substance, a PCR product is electrophoresed on an agarose gel, and ethidium is used.
- a method for detecting double-stranded DNA by staining with bromide or the like, a method for detecting the produced single-stranded or double-stranded DNA 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 chip or DNA chip in which the detection kit or device 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.
- the signal derived from the label of the detection kit or device is detected by an image detector (Typhoon 9410 (GE Healthcare), 3D-Gene (registered trademark) scanner (Toray Industries, Inc.). 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.
- Washing conditions after hybridization include, for example, a solution containing 0.5 ⁇ SSC at 30 ° C. and 0.1% SDS, and 0.2 at 30 ° C. There may be mentioned conditions such as continuous washing with a solution containing x SSC and 0.1% SDS and a 0.05 x SSC solution at 30 ° C. It is desirable that the complementary strand maintain a hybridized state with the target positive strand even when washed under such conditions.
- 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 thereof include a chain consisting of a base sequence having at least 90% or at least 95% homology.
- 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).
- TaqMan registered trademark
- MicroRNA Assays Life Technologies
- LNA registered trademark
- MicroRNA PCR Exiqon
- Ncode registered trademark
- miRNA qRT-PCT kit A commercially available measurement kit specially devised to quantitatively measure miRNA, such as (Invitrogen) may be used.
- the gene expression level may be measured using a sequencer in addition to the hybridization method described above.
- a sequencer any of the DNA sequencer as the first generation based on the Sanger method, the second generation with a short read size, and the third generation with a long read size can be used (second generation and third generation). Also referred to herein as “next generation sequencer”, including generational sequencers).
- the next-generation sequence is a method for acquiring sequence information using a next-generation sequencer, and is characterized in that a huge number of sequence reactions can be performed in parallel as compared to the Sanger method (for example, Rick Kamps et al. , Int. J. Mol. Sci., 2017, 18 (2), p. 308 and Int. Neurour. J., 2016, 20 (Suppl. 2), S76-83).
- the Sanger method for example, Rick Kamps et al. , Int. J. Mol. Sci., 2017, 18 (2), p. 308 and Int. Neurour. J., 2016, 20 (Suppl. 2), S76-83.
- an adapter sequence having a predetermined base sequence is added, and then, before or after the addition of the sequence, the total RNA is reverse-transcribed to cDNA.
- a cDNA derived from a specific target miRNA may be amplified or concentrated by PCR or using a probe or the like.
- the details of the subsequent sequencing step vary depending on the type of the next-generation sequencer, but typically, the sequencing reaction is performed by connecting to a substrate via an adapter sequence and using the adapter sequence as a priming site. For details of the sequence reaction, see, for example, Rick Kamps et al. See (above). Finally, data output is performed. In this step, a collection of sequence information (reads) obtained by the sequence reaction is obtained.
- a target miRNA can be specified based on sequence information, and the expression level can be measured based on the number of reads having the sequence of the target miRNA.
- 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 a target gene or expression level of a gene in a subject-derived specimen, and suffers from a subject (or patient) -derived specimen and bladder cancer known to have bladder cancer.
- discriminant discriminant function
- a method of detecting (or assisting in) detection of bladder cancer in a subject, comprising substituting the expression level of a target gene in a specimen of the subject and thereby assessing the presence or absence of bladder cancer provide.
- the present invention further provides in vitro expression levels of target genes in a plurality of samples that are known to determine or evaluate that a subject contains bladder cancer and / or does not contain bladder cancer.
- the first step of measuring in step 2 the second step of creating a discriminant using the measured value of the expression level of the target gene obtained in the first step as a teacher sample, the target in the subject-derived specimen.
- a fourth step of substituting the value and determining or evaluating that the subject includes bladder cancer or does not include bladder cancer based on the result obtained from the discriminant is included.
- the target gene may be detectable by the polynucleotide, the polynucleotide contained in the kit or chip, and the mutant or fragment thereof.
- the discriminant is an arbitrary discriminant analysis method that can create a discriminant that discriminates the presence or absence of bladder cancer, for example, Fisher's discriminant analysis, nonlinear discriminant analysis by Mahalanobis distance, Discriminants can be created using neural networks, Support Vector Machine (SVM), logistic regression analysis (especially, logistic regression analysis using LASSO (Least Absolute Shrinkage and Selection Operator) method), k-neighbor method, decision tree, etc.
- SVM Support Vector Machine
- logistic regression analysis especially, logistic regression analysis using LASSO (Least Absolute Shrinkage and Selection Operator) method
- k-neighbor method decision tree, etc.
- the present invention is not limited to these specific examples.
- Linear discriminant analysis is a method of discriminating group affiliation 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
- w0 is a constant term.
- the value obtained by the discriminant is called a discriminant score, and the measured value of a newly given data set is substituted into the discriminant as an explanatory variable, and the grouping can be discriminated by the code of the discriminant score.
- 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, WN et al., Modern Applied Statistics with S. Fourth edition. Springer., 2002). In Fisher's discriminant analysis, 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 are the inter-class variance and intra-class variance when the data is projected in the direction of the vector w, respectively, and the discriminant coefficient wi 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, p 273-297).
- 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 the 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.
- Logistic regression is a multivariate analysis method that uses one categorical variable (binary variable) as an objective variable and predicts the probability of occurrence using a plurality of explanatory variables.
- the LASSO (Least Absolute Shrinkage and Selection Operator) method is one of the variable selection and adjustment methods when there are many observed variables, and was proposed by Tibshirani IV (Tibshirani R., 1996, JRoSt. Ser B, 58, p267-88).
- the LASSO method is characterized by introducing a penalty term when estimating a regression coefficient, thereby suppressing overfitting to the model and estimating some regression coefficients to zero.
- the regression coefficient is estimated so as to maximize the log likelihood function expressed by Equation 8.
- methods such as neural network, k-neighbor method, decision tree, and logistic regression analysis are used to determine or evaluate whether a subject-derived specimen contains bladder cancer or does not contain bladder cancer. Can be selected.
- the method of the present invention comprises, for example, the following steps (a), (b) and (c):
- a polynucleotide, kit or DNA for detection according to the present invention is used to detect the expression level of a target gene in a specimen already known to be derived from a bladder cancer patient and to be a subject not containing bladder cancer. Measuring with a tip, (B) creating a discriminant of the above formulas 1 to 3, 5 and 6 from the measured 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 DNA chip according to the present invention, and these are expressed in the discriminant created in (b).
- 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 between the bladder cancer patient and the subject not suffering from bladder cancer according to the present invention is, for example, a gene expression level selected from the following (1) or (2) : (1) suffering from bladder cancer patients and bladder cancer measured by any one of DNAs containing 15 or more consecutive bases in the base sequence represented by any of SEQ ID NOs: 1 to 228 or its complementary sequence Measured by either gene expression level in the serum of an untested subject; or (2) DNA containing 15 or more consecutive bases in the base sequence represented by any of SEQ ID NOS: 229 to 243 or its complementary sequence Of gene expression in sera of patients with and without bladder cancer.
- a discriminant using one or more gene expression levels as an explanatory variable is necessary as a method for determining or evaluating whether or not the subject has bladder cancer for a subject-derived specimen It is.
- a gene with a clear difference in the expression level between two groups consisting of a bladder cancer patient group and a healthy subject group is used as a discriminant. It is necessary to use it.
- the gene used for the explanatory variable of the discriminant is determined as follows. First, using the data set of the exhaustive gene expression level of the bladder cancer patient group as the learning group and the exhaustive gene expression level of the subject group not suffering from bladder cancer, the P value of the t-test, which is parametric analysis, Using the P value of Mann-Whitney U test, which is a parametric analysis, or the P value of Wilcoxon test, the magnitude of the difference in the expression level of each gene between the two groups is determined.
- 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 of each gene expression level (Fold change) between the gene expression level of the bladder cancer patient group and the gene expression level of the subject group not suffering from bladder cancer instead of the test. ) May be calculated, and the gene used for the explanatory variable of the discriminant may be selected. Moreover, even if a ROC curve is created using the gene expression levels of the bladder cancer patient group and the subject group not suffering from bladder cancer, 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).
- the gene expression level of another independent bladder cancer patient or subject not suffering from bladder cancer is substituted into the explanatory variable, and this independent bladder cancer patient or bladder cancer is affected.
- the discrimination result of the group to which the subject who does not belong is calculated. That is, a diagnostic gene set capable of detecting more unbiased bladder cancer by evaluating a discriminant constructed using the found diagnostic gene set and the diagnostic gene set in an independent sample group, and A method for identifying bladder cancer can be found.
- the Split-sample method for evaluating the discriminating performance (generalization) of the discriminant.
- 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 group belongs, and the discrimination performance is evaluated.
- the selection of genes and the creation of discriminants by statistical tests are performed using all samples, and the newly prepared samples are discriminated by the discriminants to determine accuracy, sensitivity, and specificity. And the discrimination performance can be evaluated.
- the present invention relates to a polynucleotide for detection or disease diagnosis useful for diagnosis and treatment of bladder cancer, a method for detecting bladder cancer using the polynucleotide, and a bladder cancer detection kit and device containing the polynucleotide.
- a wasteful additional examination may be performed by misidentifying a non-bladder cancer patient as a bladder cancer patient, or a treatment opportunity may be lost by overlooking the bladder cancer patient.
- the present invention is capable of correctly discriminating bladder cancer regardless of stage, invasion degree, histological atypia, initial / recurrence with a non-invasive and small amount of specimen, that is, from a bladder cancer marker with high accuracy.
- a disease diagnosis kit or device useful for bladder cancer diagnosis and treatment, and a bladder cancer determination (or detection) method is disclosed.
- a diagnostic gene set is defined as a diagnostic gene set.
- a discriminant is constructed by using the expression level of the diagnostic gene set in a sample derived from a patient determined to be bladder cancer as a result of tissue diagnosis and a sample derived from a subject not suffering from bladder cancer.
- a discriminant is constructed by using the expression level of the diagnostic gene set in a sample derived from a patient determined to be bladder cancer as a result of tissue diagnosis and a sample derived from a subject not suffering from bladder cancer.
- bladder cancer can be detected with high sensitivity, so that bladder cancer can be detected at an early stage.
- early treatment is possible, which can lead to a significant improvement in survival rate.
- lost treatment opportunities due to overlooking bladder cancer patients and non-bladder This makes it possible to avoid unnecessary additional tests by misidentifying cancer patients as bladder cancer patients.
- the stage of bladder cancer patients is 57 for stage 0a, 10 for stage 0is, 121 for stage I, 15 for stage II, 2 for stage III, 14 for stage IV, and 97 for stage unknown there were.
- T classification which shows the penetration depth in the wall of a primary tumor in TNM classification was 300 people less than T2, 90 people more than T2, and 2 unknown.
- the histological grade of bladder cancer was 315 for the high grade and 77 for the low grade.
- RNA extraction reagent from liquid sample kit (Toray Co., Ltd. (Japan) was used, and the company's RNA extraction reagent was used.
- Total RNA was obtained according to the defined protocol.
- RNA obtained from a total of 1303 sera as samples was fluorescently labeled with miRNA using 3D-Gene (registered trademark) miRNA Labeling kit (Toray Industries, Inc.) based on the protocol established by the company.
- 3D-Gene registered trademark
- Human miRNA Oligo chip equipped with a probe having a sequence complementary to 2,565 kinds of miRNAs among miRNAs registered in miRBBase release 21 ) 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 was converted to a logarithmic value with a base of 2 to obtain the gene expression level, the blank value was subtracted, and the missing value was replaced with a signal value of 0.1. As a result, comprehensive miRNA gene expression levels were obtained for the above 1303 sera.
- 3D-Gene registered trademark
- 3D-Gene registered trademark
- Extraction Toray Industries, Inc.
- Samples used for discriminant analysis of bladder cancer were extracted as follows.
- benign osteosoft tissue, milk benign disease, benign ovarian tumor, prostate benign disease, uterine fibroids, benign brain tumor patients are collectively referred to as “benign disease patients”, lung cancer, colon cancer, and esophagus.
- Gastric cancer, liver cancer, biliary tract cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, uterine sarcoma, malignant brain tumor, malignant bone and soft tissue tumor (Table 2).
- a total of 911 patients including 392 bladder cancer patients as a positive sample group, 611 cancer patients other than the above-mentioned bladder cancer, 200 benign disease patients, and 100 healthy subjects as a negative sample group (Table 2). It was. 2/3 of each sample group was assigned to the learning sample group, and 1/3 of the sample group was assigned to the verification sample group (Table 4). That is, 261 bladder cancer patients, 408 cancer patients other than bladder cancer, 133 benign disease patients, and 67 healthy persons are used as a learning sample group, 131 bladder cancer patients, cancer other than bladder cancer 203 test samples, 67 patients with benign disease, and 33 healthy subjects were used as a verification sample group (Table 4).
- Samples used for discriminant analysis (Example 4) of bladder cancer patients with TNM classification T2 or higher and bladder cancer patients with less than T2 were extracted as follows. First, the positive sample group was 90 bladder cancer patients less than T2, and the negative sample group was 300 bladder cancer patients T2 or more. Furthermore, 58 patients with bladder cancer less than T2, 137 patients with bladder cancer of T2 or more are used as a learning sample group, 32 patients with bladder cancer of less than T2, and 163 patients with bladder cancer of T2 or more are verified sample groups. (Table 5).
- Example 1 ⁇ Bladder cancer discriminant analysis with one miRNA or a combination of 2 to 5>
- a discriminant based on 1 to 5 genetic markers was created and verified using a group of learning samples (Table 4) including patients with bladder cancer and subjects without bladder cancer.
- a genetic marker that can detect bladder cancer by evaluating the discrimination performance in the sample group (Table 4) and extracting the genes used in 1 to 5 discriminants of 50 formulas with the highest discrimination performance and a total of 250 discriminants 149 were acquired (Table 6).
- 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. Further, in order to obtain a more reliable diagnostic marker, 50 in either a positive sample group (bladder cancer patient) or a negative sample group (cancer patients other than bladder cancer, benign disease patients and normal subjects) Only 384 genes having a gene expression level of 2 6 or more in 2% or more samples were analyzed.
- Fisher's discriminant analysis was performed on one or a combination of 2 to 5 of the 384 gene expression level measurement values, and a discriminant for discriminating the presence or absence of bladder cancer was constructed.
- a search for a discriminant having high discrimination performance was performed by the modified greedy algorithm.
- the accuracy, sensitivity, and specificity in the verification sample group were calculated using the discriminant created above, and the discrimination performance was verified with an independent sample. The results are shown below for each number of genes used for discrimination.
- Example 1-1 As a result of the above, each of the 50 formulas with one gene having the highest discrimination performance was obtained. Table 7-1 shows this discriminant and its threshold value (which discriminates positive / negative. Positive value is greater than or equal to threshold). Sensitivity, specificity, accuracy, AUC, and gene used for discriminant in the learning sample group and verification sample group. The genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer.
- the measured value is input to the discriminant represented by 1 to obtain a discriminant score, 261 bladder cancer patients (positive sample group) in the learning sample group, and 608 subjects not suffering from bladder cancer (negative)
- the discrimination score of (sample group) was plotted, and it was shown in FIG. 2A that both groups were significantly separated.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0.19 is determined to be affected by bladder cancer, and a small score is determined to be not affected by bladder cancer. This result was reproducible even in the verification sample group (FIG. 2B).
- the discrimination score according to the disease type in the verification sample group is plotted, and it is shown in FIG. 3 that it is preferentially separated from bladder cancer regardless of the disease type.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- the discrimination score is shown, and it can be confirmed that bladder cancer of any category can be detected with high accuracy.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- Example 1-2 As a result of the above, each of 50 formulas with high discrimination performance was obtained with 2 gene combinations.
- the discriminant and its threshold value (discriminate positive / negative. Positive value above threshold is positive).
- Sensitivity, specificity, accuracy, AUC, and genes used for discriminant in learning sample group and verification sample group are shown in Tables 8-1 and 2-2. Show.
- the genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer. The accuracy was 84% to 89%, and the sensitivity to discriminate bladder cancer was 86% to 96%, indicating very high discrimination performance (Table 8-2).
- Table 8-3 shows the discriminant formulas and thresholds for discriminating with two gene combinations.
- Example 1-3 As a result of the above, each of 50 formulas with the highest discrimination performance was obtained with 3 gene combinations. Tables 9-1 and 2 show the sensitivity, specificity, accuracy, AUC, and genes used for the discriminant in this discriminant and its threshold (positive / negative is discriminated; positive above threshold). Show. The genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer.
- the measured value is input into the discriminant represented by 1 to obtain a discriminant score, 261 bladder cancer patients (positive sample group) in the learning sample group, and 608 subjects who are not affected by bladder cancer (negative)
- the discrimination score of (sample group) was plotted, and it was shown in FIG. 5A that both groups were significantly separated.
- the vertical axis of the figure shows the discrimination score, and a score greater than the threshold value ⁇ 0.03 is determined to have bladder cancer, and a small score is determined to have no bladder cancer. This result was reproducible even in the verification sample group (FIG. 5B).
- the disease-specific discrimination score plot in the verification sample group was plotted, and it was shown in FIG. 6 that it was preferentially separated from bladder cancer regardless of the disease type.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- the discrimination score is shown, and it can be confirmed that bladder cancer of any category can be detected with high accuracy.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- Example 1-4 As a result of the above, 50 formulas each having a high discrimination performance with 4 gene combinations were obtained.
- Table 10-1 and Table 2 show the discriminant and its threshold value (which discriminates between positive and negative. The positive value is greater than or equal to the threshold). Show.
- the genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer.
- the measured value is input into the discriminant represented by 1 to obtain a discriminant score, 261 bladder cancer patients (positive sample group) in the learning sample group, and 608 subjects who are not affected by bladder cancer (negative)
- the discrimination score of (sample group) was plotted, and it was shown in FIG. 8A that both groups were significantly separated.
- the vertical axis of the figure shows the discrimination score, and a score greater than the threshold value of ⁇ 0.18 is determined to have bladder cancer, and a small score is determined to have no bladder cancer. This result was reproducible even in the verification sample group (FIG. 8B).
- the disease-specific discrimination score plots in the verification sample group are shown in FIG. 9 to be preferentially separated from bladder cancer regardless of the disease type.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- the discrimination score is shown, and it can be confirmed that bladder cancer of any category can be detected with high accuracy.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- Example 1-5 As a result of the above, each of 50 formulas with the highest discrimination performance was obtained with 5 gene combinations. Table 11-1 and Table 2 show the discriminant and its threshold value (which discriminates positive / negative. Positive value is greater than or equal to the threshold). Show. The genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer.
- the measured value is input into the discriminant represented by 1 to obtain a discriminant score, 261 bladder cancer patients (positive sample group) in the learning sample group, and 608 subjects who are not affected by bladder cancer (negative)
- the discrimination score of (sample group) was plotted, and it was shown in FIG. 11A that both groups were significantly separated.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value of ⁇ 0.12 is determined to have bladder cancer, and a small score is determined to have no bladder cancer. This result was reproducible even in the verification sample group (FIG. 11B).
- the disease-specific discrimination score plots in the verification sample group are shown in FIG.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- the discrimination score is shown, and it can be confirmed that bladder cancer of any category can be detected with high accuracy.
- the vertical axis of the figure shows the discrimination score, and a score higher than the threshold value 0 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- the polynucleotides shown in Tables 6 to 11 obtained in Examples 1-1 to 1-5 are specific to bladder cancer patients from cancer patients other than bladder cancer, benign disease patients, and healthy individuals. It can be said that it is a gene group that can be discriminated automatically. In addition, it was shown that higher bladder cancer discrimination performance can be obtained when a plurality of polynucleotides are combined than a single polynucleotide or a smaller number of polynucleotides.
- the combination of a plurality of polynucleotides that can be used for detection of bladder cancer is not limited to the above combination, and may be any plurality of polynucleotides.
- Example 2 ⁇ Bladder cancer discriminant analysis by 1 miRNA or a combination of 2 to 104>
- a discriminant using 1 to 104 gene markers is determined using a group of learning specimens (Table 4) including cancer patients other than bladder cancer, benign disease patients, and healthy individuals. Once created, bladder cancer is detected by evaluating the discrimination performance in the verification sample group (Table 4) and extracting genes used in discriminants combining up to 104 genes that showed high discrimination accuracy Possible genetic markers were obtained (Table 12).
- 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. Further, in order to obtain a more reliable diagnostic marker, 50 in either a positive sample group (bladder cancer patient) or a negative sample group (cancer patients other than bladder cancer, benign disease patients and normal subjects) Only 384 genes having a gene expression level of 2 6 or more in 2% or more samples were analyzed.
- a logistic regression analysis by LASSO method is performed from the above 384 gene expression level measurement values, and a discriminant combining a plurality of miRNAs from one is created. Whether 104 combinations are bladder cancer or not We constructed a discriminant that discriminates with high accuracy. Using this discriminant, the accuracy, sensitivity, and specificity in the verification sample group were calculated, and the discrimination performance was verified with an independent sample. Details are shown below for each number of genes used for discrimination.
- Example 2-1 As a result of the above, the discriminant by the combination of three genes and the threshold value (positive / negative is discriminated.
- the threshold value or more is positive).
- the genes are shown in Tables 13-1 and 13. The genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer.
- the measured value is input to the discriminant represented by the discriminant in Table 13-3 to obtain y, and the value obtained by substituting y into Equation 9 is plotted as the discriminant score according to the disease type in the test sample group.
- FIG. 14 shows that it is preferentially separated from bladder cancer regardless of type. The vertical axis of the figure indicates the discrimination score, and a score higher than the threshold value 0.5 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- Example 2-2 As a result of the above, the discriminant by the combination of 10 genes and the threshold (positive / negative is discriminated. The threshold or higher is positive) are used for the sensitivity, specificity, accuracy, AUC and discriminant in the learning sample group and the verification sample group.
- the genes are shown in Table 14-1. The genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer.
- the measured value is input to the discriminant represented by the discriminant of Table 14-2 to obtain y, and the value obtained by substituting y into Equation 9 is plotted as the discriminant score according to the disease type in the test sample group.
- FIG. 16 shows that it is preferentially separated from bladder cancer regardless of type.
- the vertical axis of the figure indicates the discrimination score, and a score higher than the threshold value 0.5 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- Example 2-3 As a result of the above, the discriminant by the combination of 104 genes and the threshold value (positive / negative is discriminated.
- the threshold value or more is positive).
- the genes are shown in Table 15-1. The genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer.
- the measured value is input to the discriminant represented by the discriminant in Table 15-2 to obtain y, and the value obtained by substituting y into Equation 9 is plotted as the discriminant score according to the disease type in the test sample group.
- FIG. 18 shows that it is preferentially separated from bladder cancer regardless of type. The vertical axis of the figure indicates the discrimination score, and a score higher than the threshold value 0.5 is determined to have bladder cancer, and a small score is determined to have no bladder cancer.
- Example 2-4 As a result of the above, the discriminant expression based on the combination of 1 gene or 2 to 103 genes and the threshold (positive / negative is discriminated. The threshold or more is positive.) Sensitivity, specificity, accuracy, AUC in the learning sample group and the verification sample group The genes used in the discriminant are shown in Table 16-1. The genes included in these discriminants were selected as diagnostic markers capable of discriminating between bladder cancer patients and subjects not suffering from bladder cancer. Table 16-2 shows the discriminant formulas and thresholds for performing discrimination based on combinations of 1 gene or 2 to 104 genes (the combinations of 104 genes are shown in Table 15-1 as described above).
- Example 3 ⁇ Comparison of miRNA expression levels in serum between bladder cancer patients and cancer patients other than bladder cancer, benign disease patients, and healthy individuals>
- a group of learning samples in which a sample of the gene expression was measured in the above-mentioned reference example, comparing the serum miRNA expression levels in cancer patients other than bladder cancer, benign disease patients, and healthy subjects in the bladder cancer patients (Table 1). 4).
- 261 bladder cancer patients as a positive sample group, 408 cancer patients other than bladder cancer as a negative sample group, 133 benign disease patients, and 67 healthy subjects The miRNA expression levels of human learning sample groups were combined and normalized by global normalization.
- 89 diagnostic markers capable of detecting bladder cancer were obtained by extracting genes with corrected P values of 0.01 or less and an absolute value of Fold change of 0.5 or more as expression variation genes (Table 17). ).
- Table 17 shows the average value of the expression level of the positive sample group and the negative sample group of the selected gene, SD, Bonferroni corrected P value, and absolute value of Fold change.
- genes newly found as markers for examining the presence or absence of bladder cancer are SEQ ID NOs: 1, 2, 3, 4, 5, 11, 12, 15, 17, 19, 20, 21, 26, 27, 28, 31, 35, 36, 41, 44, 45, 47, 48, 49, 50, 53, 59, 65, 67, 72, 73, 74, 76, 80, 82, 83, 85, 88, 89, 95, 96, 98, 99, 104, 107, 108, 119, 120, 121, 125, 126, 128, 130, 132, 133, 135, 136, 137, 138, 142, 146, 148, 149, 150, 152, 154, 155, 156, 161, 164, 169, 172, 174, 176, 179, 182, 198, 201, 204, 209, 219, 222, 223, 224, 226 A polynucleotide consisting of the nucleotide sequence.
- the TNM classification indicates the depth of penetration of the primary tumor in the wall
- the treatment method is T2 or higher, which is a target for total cystectomy, and T2, which is a target for treatment such as endoscope or BCG injection therapy.
- the miRNA expression levels of the T2 or more and less than T2 groups obtained in the above Reference Example were combined and normalized by global normalization. Furthermore, in order to obtain a more reliable diagnostic marker, only 398 genes having a gene expression level of 2 6 or more in 50% or more of specimens in either the group of T2 or more and the group of less than T2 are analyzed. Targeted.
- the genes included in these discriminants were selected as diagnostic markers capable of distinguishing between bladder cancer patients of T2 or more and bladder cancer patients of less than T2.
- the accuracy in the verification sample group is 43% to 78%, the sensitivity is 13% to 81%, the specificity is 36% to 91%, and the miRNA marker can be discriminated alone or in combination depending on the priority of sensitivity and specificity. The possibility was shown.
- Example 5 (miRNA common to Examples 1 to 3)
- a gene common to Examples 1 and 2 was extracted, and bladder cancer was extracted. 43 gene markers with higher versatility were detected (Table 20).
- genes common to Examples 1 and 3 were extracted to obtain 62 more versatile gene markers capable of detecting bladder cancer (Table 21).
- 30 genes markers with higher versatility capable of detecting bladder cancer were obtained by extracting genes common to Examples 2 and 3 (Table 22).
- genes common to all of Examples 1 to 3 were extracted, and 23 more versatile gene markers capable of detecting bladder cancer were obtained (Table 23). It can be said that the genes shown in Tables 20 to 23 are highly versatile markers that can be used in common in various analysis techniques and can detect bladder cancer with high versatility.
- Example 6 ⁇ Bladder cancer discrimination analysis for the purpose of discrimination from other cancers>
- 392 bladder cancer patients and 40 cancer patients other than bladder cancer were included in each of the reference examples, 0 for the uterine sarcoma patient group, 100 for healthy persons, a total of 972. Human serum was analyzed. Half of each sample group was assigned to the learning sample group, and the remaining half of the sample group was assigned to the verification sample group (Table 24).
- a 1 to 9 gene marker is used using a group of learning specimens including a bladder cancer patient and healthy subjects and cancer patients other than bladder cancer as subjects who do not suffer from bladder cancer.
- the discriminant performance is evaluated in the verification sample group, and the genes used for the discriminant of the total of 9 formulas that show first place in the discriminant performance with 1 to 9 gene combinations are extracted.
- 18 genetic markers capable of detecting bladder cancer were obtained (Table 25).
- the miRNA expression levels of the learning sample group and the verification sample group obtained in the same manner as in the above reference example were combined and normalized by global normalization. Furthermore, in order to obtain a more reliable diagnostic marker, in either a positive sample group (bladder cancer patient) or a negative sample group (cancer patients other than bladder cancer, benign disease patients and normal subjects), 50 Only 386 genes having a gene expression level of 2 6 or more in 2% or more samples were analyzed. Next, Fisher's discriminant analysis was performed on 1 to 9 combinations including the 386 gene expression level measurement values, and a discriminant for determining the presence or absence of bladder cancer was constructed. At this time, a search for a discriminant having high discrimination performance was performed by the modified greedy algorithm.
- FIG. 20 shows the ROC curve of the learning sample group and the verification sample group in the combination of one or seven miRNAs
- FIG. 21 shows the disease type discrimination score plot for seven miRNAs.
- bladder cancers of various tissue types and degrees of progression can be effectively detected by a simple and inexpensive method, thereby enabling early detection, diagnosis and treatment of bladder cancer. Further, according to the method of the present invention, bladder cancer can be detected in a minimally invasive manner using patient blood, so that bladder cancer can be detected easily and quickly.
Abstract
Description
すなわち、本発明は、以下の態様を含む。
(1)膀胱がんマーカーである、miR-6087、miR-1185-1-3p、miR-1185-2-3p、miR-1193、miR-1199-5p、miR-1225-5p、miR-1227-5p、miR-1228-3p、miR-1228-5p、miR-1237-5p、miR-1238-5p、miR-1247-3p、miR-1268a、miR-1268b、miR-1273g-3p、miR-128-2-5p、miR-1343-3p、miR-1343-5p、miR-1470、miR-17-3p、miR-187-5p、miR-1908-3p、miR-1908-5p、miR-1909-3p、miR-1915-3p、miR-210-5p、miR-24-3p、miR-2467-3p、miR-2861、miR-296-3p、miR-29b-3p、miR-3131、miR-3154、miR-3158-5p、miR-3160-5p、miR-3162-5p、miR-3178、miR-3180-3p、miR-3184-5p、miR-3185、miR-3194-3p、miR-3195、miR-3197、miR-320a、miR-320b、miR-328-5p、miR-342-5p、miR-345-3p、miR-3616-3p、miR-3619-3p、miR-3620-5p、miR-3621、miR-3622a-5p、miR-3648、miR-3652、miR-3656、miR-3663-3p、miR-3679-5p、miR-371b-5p、miR-373-5p、miR-3917、miR-3940-5p、miR-3960、miR-4258、miR-4259、miR-4270、miR-4286、miR-4298、miR-4322、miR-4327、miR-4417、miR-4419b、miR-4429、miR-4430、miR-4433a-3p、miR-4436b-5p、miR-4443、miR-4446-3p、miR-4447、miR-4448、miR-4449、miR-4454、miR-4455、miR-4459、miR-4462、miR-4466、miR-4467、miR-4480、miR-4483、miR-4484、miR-4485-5p、miR-4488、miR-4492、miR-4505、miR-4515、miR-4525、miR-4534、miR-4535、miR-4633-3p、miR-4634、miR-4640-5p、miR-4649-5p、miR-4651、miR-4652-5p、miR-4655-5p、miR-4656、miR-4658、miR-4663、miR-4673、miR-4675、miR-4687-3p、miR-4687-5p、miR-4690-5p、miR-4695-5p、miR-4697-5p、miR-4706、miR-4707-3p、miR-4707-5p、miR-4708-3p、miR-4710、miR-4718、miR-4722-5p、miR-4725-3p、miR-4726-5p、miR-4727-3p、miR-4728-5p、miR-4731-5p、miR-4736、miR-4739、miR-4740-5p、miR-4741、miR-4750-5p、miR-4755-3p、miR-4763-3p、miR-4771、miR-4783-3p、miR-4783-5p、miR-4787-3p、miR-4792、miR-498、miR-5008-5p、miR-5010-5p、miR-504-3p、miR-5195-3p、miR-550a-5p、miR-5572、miR-5739、miR-6075、miR-6076、miR-6088、miR-6124、miR-6131、miR-6132、miR-614、miR-615-5p、miR-619-5p、miR-642b-3p、miR-6510-5p、miR-6511a-5p、miR-6515-3p、miR-6515-5p、miR-663b、miR-6716-5p、miR-6717-5p、miR-6722-3p、miR-6724-5p、miR-6726-5p、miR-6737-5p、miR-6741-5p、miR-6742-5p、miR-6743-5p、miR-6746-5p、miR-6749-5p、miR-6760-5p、miR-6762-5p、miR-6765-3p、miR-6765-5p、miR-6766-3p、miR-6766-5p、miR-6771-5p、miR-6774-5p、miR-6777-5p、miR-6778-5p、miR-6780b-5p、miR-6781-5p、miR-6782-5p、miR-6784-5p、miR-6785-5p、miR-6787-5p、miR-6789-5p、miR-6791-5p、miR-6794-5p、miR-6800-5p、miR-6802-5p、miR-6803-5p、miR-6812-5p、miR-6816-5p、miR-6819-5p、miR-6821-5p、miR-6826-5p、miR-6831-5p、miR-6836-3p、miR-6840-3p、miR-6842-5p、miR-6850-5p、miR-6861-5p、miR-6869-5p、miR-6870-5p、miR-6877-5p、miR-6879-5p、miR-6880-3p、miR-6880-5p、miR-6885-5p、miR-6887-5p、miR-7107-5p、miR-7108-3p、miR-7109-5p、miR-711、miR-7113-3p、miR-7150、miR-744-5p、miR-7975、miR-7977、miR-8052、miR-8069、miR-8073、miR-887-3p、miR-937-5pから選択される少なくとも1つのポリヌクレオチド、又は該ポリヌクレオチドの相補鎖と特異的に結合可能な核酸を含む、膀胱がんの検出用キット。
(a)配列番号1~228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1~228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1~228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1~228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、(1)に記載のキット。
(f)配列番号229~243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229~243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229~243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229~243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、(3)に記載のキット。
(a)配列番号1~228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1~228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1~228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1~228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、(5)に記載のデバイス。
(f)配列番号229~243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229~243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229~243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229~243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、(7)に記載のデバイス。
(a)配列番号1~228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1~228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1~228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1~228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、(11)又は(12)に記載の方法。
(f)配列番号229~243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229~243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229~243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229~243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、(14)に記載の方法。
本明細書中で使用する用語は、以下の定義を有する。
ヌクレオチド、ポリヌクレオチド、DNA、RNAなどの略号による表示は、「塩基配列又はアミノ酸配列を含む明細書等の作成のためのガイドライン」(日本国特許庁編)及び当技術分野における慣用に従うものとする。
1.膀胱がんの標的核酸
本発明の上記定義の膀胱がん検出用の核酸プローブ又はプライマーを使用して、膀胱がん又は膀胱がん細胞の存在及び/又は不存在を検出するための、膀胱がんマーカーとしての主要な標的核酸には、miR-6087、miR-1185-1-3p、miR-1185-2-3p、miR-1193、miR-1199-5p、miR-1225-5p、miR-1227-5p、miR-1228-3p、miR-1228-5p、miR-1237-5p、miR-1238-5p、miR-1247-3p、miR-1268a、miR-1268b、miR-1273g-3p、miR-128-2-5p、miR-1343-3p、miR-1343-5p、miR-1470、miR-17-3p、miR-187-5p、miR-1908-3p、miR-1908-5p、miR-1909-3p、miR-1915-3p、miR-210-5p、miR-24-3p、miR-2467-3p、miR-2861、miR-296-3p、miR-29b-3p、miR-3131、miR-3154、miR-3158-5p、miR-3160-5p、miR-3162-5p、miR-3178、miR-3180-3p、miR-3184-5p、miR-3185、miR-3194-3p、miR-3195、miR-3197、miR-320a、miR-320b、miR-328-5p、miR-342-5p、miR-345-3p、miR-3616-3p、miR-3619-3p、miR-3620-5p、miR-3621、miR-3622a-5p、miR-3648、miR-3652、miR-3656、miR-3663-3p、miR-3679-5p、miR-371b-5p、miR-373-5p、miR-3917、miR-3940-5p、miR-3960、miR-4258、miR-4259、miR-4270、miR-4286、miR-4298、miR-4322、miR-4327、miR-4417、miR-4419b、miR-4429、miR-4430、miR-4433a-3p、miR-4436b-5p、miR-4443、miR-4446-3p、miR-4447、miR-4448、miR-4449、miR-4454、miR-4455、miR-4459、miR-4462、miR-4466、miR-4467、miR-4480、miR-4483、miR-4484、miR-4485-5p、miR-4488、miR-4492、miR-4505、miR-4515、miR-4525、miR-4534、miR-4535、miR-4633-3p、miR-4634、miR-4640-5p、miR-4649-5p、miR-4651、miR-4652-5p、miR-4655-5p、miR-4656、miR-4658、miR-4663、miR-4673、miR-4675、miR-4687-3p、miR-4687-5p、miR-4690-5p、miR-4695-5p、miR-4697-5p、miR-4706、miR-4707-3p、miR-4707-5p、miR-4708-3p、miR-4710、miR-4718、miR-4722-5p、miR-4725-3p、miR-4726-5p、miR-4727-3p、miR-4728-5p、miR-4731-5p、miR-4736、miR-4739、miR-4740-5p、miR-4741、miR-4750-5p、miR-4755-3p、miR-4763-3p、miR-4771、miR-4783-3p、miR-4783-5p、miR-4787-3p、miR-4792、miR-498、miR-5008-5p、miR-5010-5p、miR-504-3p、miR-5195-3p、miR-550a-5p、miR-5572、miR-5739、miR-6075、miR-6076、miR-6088、miR-6124、miR-6131、miR-6132、miR-614、miR-615-5p、miR-619-5p、miR-642b-3p、miR-6510-5p、miR-6511a-5p、miR-6515-3p、miR-6515-5p、miR-663b、miR-6716-5p、miR-6717-5p、miR-6722-3p、miR-6724-5p、miR-6726-5p、miR-6737-5p、miR-6741-5p、miR-6742-5p、miR-6743-5p、miR-6746-5p、miR-6749-5p、miR-6760-5p、miR-6762-5p、miR-6765-3p、miR-6765-5p、miR-6766-3p、miR-6766-5p、miR-6771-5p、miR-6774-5p、miR-6777-5p、miR-6778-5p、miR-6780b-5p、miR-6781-5p、miR-6782-5p、miR-6784-5p、miR-6785-5p、miR-6787-5p、miR-6789-5p、miR-6791-5p、miR-6794-5p、miR-6800-5p、miR-6802-5p、miR-6803-5p、miR-6812-5p、miR-6816-5p、miR-6819-5p、miR-6821-5p、miR-6826-5p、miR-6831-5p、miR-6836-3p、miR-6840-3p、miR-6842-5p、miR-6850-5p、miR-6861-5p、miR-6869-5p、miR-6870-5p、miR-6877-5p、miR-6879-5p、miR-6880-3p 、miR-6880-5p、miR-6885-5p、miR-6887-5p、miR-7107-5p、miR-7108-3p、miR-7109-5p、miR-711、miR-7113-3p、miR-7150、miR-744-5p、miR-7975、miR-7977、miR-8052、miR-8069、miR-8073、miR-887-3p、miR-937-5p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。さらにこれらのmiRNAと組み合わせることができる他の膀胱がんマーカー、すなわち、miR-1202、miR-1207-5p、miR-1246、miR-1254、miR-135a-3p、miR-1469、miR-149-3p、miR-150-3p、miR-1914-3p、miR-191-5p、miR-423-5p、miR-663a、miR-92a-2-5p、miR-92a-3p、miR-940からなる群から選択される少なくとも1つのmiRNAも標的核酸として好ましく用いることができる。
本発明において、膀胱がんを検出するための、あるいは膀胱がんを診断するために使用可能な核酸プローブ又はプライマーは、膀胱がんの標的核酸としての、ヒト由来のmiR-6087、miR-1185-1-3p、miR-1185-2-3p、miR-1193、miR-1199-5p、miR-1225-5p、miR-1227-5p、miR-1228-3p、miR-1228-5p、miR-1237-5p、miR-1238-5p、miR-1247-3p、miR-1268a、miR-1268b、miR-1273g-3p、miR-128-2-5p、miR-1343-3p、miR-1343-5p、miR-1470、miR-17-3p、miR-187-5p、miR-1908-3p、miR-1908-5p、miR-1909-3p、miR-1915-3p、miR-210-5p、miR-24-3p、miR-2467-3p、miR-2861、miR-296-3p、miR-29b-3p、miR-3131、miR-3154、miR-3158-5p、miR-3160-5p、miR-3162-5p、miR-3178、miR-3180-3p、miR-3184-5p、miR-3185、miR-3194-3p、miR-3195、miR-3197、miR-320a、miR-320b、miR-328-5p、miR-342-5p、miR-345-3p、miR-3616-3p、miR-3619-3p、miR-3620-5p、miR-3621、miR-3622a-5p、miR-3648、miR-3652、miR-3656、miR-3663-3p、miR-3679-5p、miR-371b-5p、miR-373-5p、miR-3917、miR-3940-5p、miR-3960、miR-4258、miR-4259、miR-4270、miR-4286、miR-4298、miR-4322、miR-4327、miR-4417、miR-4419b、miR-4429、miR-4430、miR-4433a-3p、miR-4436b-5p、miR-4443、miR-4446-3p、miR-4447、miR-4448、miR-4449、miR-4454、miR-4455、miR-4459、miR-4462、miR-4466、miR-4467、miR-4480、miR-4483、miR-4484、miR-4485-5p、miR-4488、miR-4492、miR-4505、miR-4515、miR-4525、miR-4534、miR-4535、miR-4633-3p、miR-4634、miR-4640-5p、miR-4649-5p、miR-4651、miR-4652-5p、miR-4655-5p、miR-4656、miR-4658、miR-4663、miR-4673、miR-4675、miR-4687-3p、miR-4687-5p、miR-4690-5p、miR-4695-5p、miR-4697-5p、miR-4706、miR-4707-3p、miR-4707-5p、miR-4708-3p、miR-4710、miR-4718、miR-4722-5p、miR-4725-3p、miR-4726-5p、miR-4727-3p、miR-4728-5p、miR-4731-5p、miR-4736、miR-4739、miR-4740-5p、miR-4741、miR-4750-5p、miR-4755-3p、miR-4763-3p、miR-4771、miR-4783-3p、miR-4783-5p、miR-4787-3p、miR-4792、miR-498、miR-5008-5p、miR-5010-5p、miR-504-3p、miR-5195-3p、miR-550a-5p、miR-5572、miR-5739、miR-6075、miR-6076、miR-6088、miR-6124、miR-6131、miR-6132、miR-614、miR-615-5p、miR-619-5p、miR-642b-3p、miR-6510-5p、miR-6511a-5p、miR-6515-3p、miR-6515-5p、miR-663b、miR-6716-5p、miR-6717-5p、miR-6722-3p、miR-6724-5p、miR-6726-5p、miR-6737-5p、miR-6741-5p、miR-6742-5p、miR-6743-5p、miR-6746-5p、miR-6749-5p、miR-6760-5p、miR-6762-5p、miR-6765-3p、miR-6765-5p、miR-6766-3p、miR-6766-5p、miR-6771-5p、miR-6774-5p、miR-6777-5p、miR-6778-5p、miR-6780b-5p、miR-6781-5p、miR-6782-5p、miR-6784-5p、miR-6785-5p、miR-6787-5p、miR-6789-5p、miR-6791-5p、miR-6794-5p、miR-6800-5p、miR-6802-5p、miR-6803-5p、miR-6812-5p、miR-6816-5p、miR-6819-5p、miR-6821-5p、miR-6826-5p、miR-6831-5p、miR-6836-3p、miR-6840-3p、miR-6842-5p、miR-6850-5p、miR-6861-5p、miR-6869-5p、miR-6870-5p、miR-6877-5p、miR-6879-5p、miR-6880-3p 、miR-6880-5p、miR-6885-5p、miR-6887-5p、miR-7107-5p、miR-7108-3p、miR-7109-5p、miR-711、miR-7113-3p、miR-7150、miR-744-5p、miR-7975、miR-7977、miR-8052、miR-8069、miR-8073、miR-887-3p、miR-937-5pあるいはそれらの組み合わせ、それらの同族体、それらの転写産物、あるいはそれらの変異体又は誘導体の存在、発現量又は存在量を定性的及び/又は定量的に測定することを可能にする。
(b)配列番号1~228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1~228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1~228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。
(g)配列番号229~243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229~243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229~243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、膀胱がん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つ又は複数を含む膀胱がん検出用キット又はデバイスを提供する。
群A:
miR-6087、miR-1185-1-3p、miR-1185-2-3p、miR-1193、miR-1199-5p、miR-1225-5p、miR-1227-5p、miR-1228-3p、miR-1228-5p、miR-1237-5p、miR-1238-5p、miR-1247-3p、miR-1268a、miR-1268b、miR-1273g-3p、miR-128-2-5p、miR-1343-3p、miR-1343-5p、miR-1470、miR-17-3p、miR-187-5p、miR-1908-3p、miR-1908-5p、miR-1909-3p、miR-1915-3p、miR-210-5p、miR-24-3p、miR-2467-3p、miR-2861、miR-296-3p、miR-29b-3p、miR-3131、miR-3154、miR-3158-5p、miR-3160-5p、miR-3162-5p、miR-3178、miR-3180-3p、miR-3184-5p、miR-3185、miR-3194-3p、miR-3195、miR-3197、miR-320a、miR-320b、miR-328-5p、miR-342-5p、miR-345-3p、miR-3616-3p、miR-3619-3p、miR-3620-5p、miR-3621、miR-3622a-5p、miR-3648、miR-3652、miR-3656、miR-3663-3p、miR-3679-5p、miR-371b-5p、miR-373-5p、miR-3917、miR-3940-5p、miR-3960、miR-4258、miR-4259、miR-4270、miR-4286、miR-4298、miR-4322、miR-4327、miR-4417、miR-4419b、miR-4429、miR-4430、miR-4433a-3p、miR-4436b-5p、miR-4443、miR-4446-3p、miR-4447、miR-4448、miR-4449、miR-4454、miR-4455、miR-4459、miR-4462、miR-4466、miR-4467、miR-4480、miR-4483、miR-4484、miR-4485-5p、miR-4488、miR-4492、miR-4505、miR-4515、miR-4525、miR-4534、miR-4535、miR-4633-3p、miR-4634、miR-4640-5p、miR-4649-5p、miR-4651、miR-4652-5p、miR-4655-5p、miR-4656、miR-4658、miR-4663、miR-4673、miR-4675、miR-4687-3p、miR-4687-5p、miR-4690-5p、miR-4695-5p、miR-4697-5p、miR-4706、miR-4707-3p、miR-4707-5p、miR-4708-3p、miR-4710、miR-4718、miR-4722-5p、miR-4725-3p、miR-4726-5p、miR-4727-3p、miR-4728-5p、miR-4731-5p、miR-4736、miR-4739、miR-4740-5p、miR-4741、miR-4750-5p、miR-4755-3p、miR-4763-3p、miR-4771、miR-4783-3p、miR-4783-5p、miR-4787-3p、miR-4792、miR-498、miR-5008-5p、miR-5010-5p、miR-504-3p、miR-5195-3p、miR-550a-5p、miR-5572、miR-5739、miR-6075、miR-6076、miR-6088、miR-6124、miR-6131、miR-6132、miR-614、miR-615-5p、miR-619-5p、miR-642b-3p、miR-6510-5p、miR-6511a-5p、miR-6515-3p、miR-6515-5p、miR-663b、miR-6716-5p、miR-6717-5p、miR-6722-3p、miR-6724-5p、miR-6726-5p、miR-6737-5p、miR-6741-5p、miR-6742-5p、miR-6743-5p、miR-6746-5p、miR-6749-5p、miR-6760-5p、miR-6762-5p、miR-6765-3p、miR-6765-5p、miR-6766-3p、miR-6766-5p、miR-6771-5p、miR-6774-5p、miR-6777-5p、miR-6778-5p、miR-6780b-5p、miR-6781-5p、miR-6782-5p、miR-6784-5p、miR-6785-5p、miR-6787-5p、miR-6789-5p、miR-6791-5p、miR-6794-5p、miR-6800-5p、miR-6802-5p、miR-6803-5p、miR-6812-5p、miR-6816-5p、miR-6819-5p、miR-6821-5p、miR-6826-5p、miR-6831-5p、miR-6836-3p、miR-6840-3p、miR-6842-5p、miR-6850-5p、miR-6861-5p、miR-6869-5p、miR-6870-5p、miR-6877-5p、miR-6879-5p、miR-6880-3p 、miR-6880-5p、miR-6885-5p、miR-6887-5p、miR-7107-5p、miR-7108-3p、miR-7109-5p、miR-711、miR-7113-3p、miR-7150、miR-744-5p、miR-7975、miR-7977、miR-8052、miR-8069、miR-8073、miR-887-3p、miR-937-5p。
群B:
miR-1202、miR-1207-5p、miR-1246、miR-1254、miR-135a-3p、miR-1469、miR-149-3p、miR-150-3p、miR-1914-3p、miR-191-5p、miR-423-5p、miR-663a、miR-92a-2-5p、miR-92a-3p、miR-940。
(2)配列番号229~243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以上の連続した塩基を含むポリヌクレオチド。
本発明はさらに、検体中のmiR-6087、miR-1185-1-3p、miR-1185-2-3p、miR-1193、miR-1199-5p、miR-1225-5p、miR-1227-5p、miR-1228-3p、miR-1228-5p、miR-1237-5p、miR-1238-5p、miR-1247-3p、miR-1268a、miR-1268b、miR-1273g-3p、miR-128-2-5p、miR-1343-3p、miR-1343-5p、miR-1470、miR-17-3p、miR-187-5p、miR-1908-3p、miR-1908-5p、miR-1909-3p、miR-1915-3p、miR-210-5p、miR-24-3p、miR-2467-3p、miR-2861、miR-296-3p、miR-29b-3p、miR-3131、miR-3154、miR-3158-5p、miR-3160-5p、miR-3162-5p、miR-3178、miR-3180-3p、miR-3184-5p、miR-3185、miR-3194-3p、miR-3195、miR-3197、miR-320a、miR-320b、miR-328-5p、miR-342-5p、miR-345-3p、miR-3616-3p、miR-3619-3p、miR-3620-5p、miR-3621、miR-3622a-5p、miR-3648、miR-3652、miR-3656、miR-3663-3p、miR-3679-5p、miR-371b-5p、miR-373-5p、miR-3917、miR-3940-5p、miR-3960、miR-4258、miR-4259、miR-4270、miR-4286、miR-4298、miR-4322、miR-4327、miR-4417、miR-4419b、miR-4429、miR-4430、miR-4433a-3p、miR-4436b-5p、miR-4443、miR-4446-3p、miR-4447、miR-4448、miR-4449、miR-4454、miR-4455、miR-4459、miR-4462、miR-4466、miR-4467、miR-4480、miR-4483、miR-4484、miR-4485-5p、miR-4488、miR-4492、miR-4505、miR-4515、miR-4525、miR-4534、miR-4535、miR-4633-3p、miR-4634、miR-4640-5p、miR-4649-5p、miR-4651、miR-4652-5p、miR-4655-5p、miR-4656、miR-4658、miR-4663、miR-4673、miR-4675、miR-4687-3p、miR-4687-5p、miR-4690-5p、miR-4695-5p、miR-4697-5p、miR-4706、miR-4707-3p、miR-4707-5p、miR-4708-3p、miR-4710、miR-4718、miR-4722-5p、miR-4725-3p、miR-4726-5p、miR-4727-3p、miR-4728-5p、miR-4731-5p、miR-4736、miR-4739、miR-4740-5p、miR-4741、miR-4750-5p、miR-4755-3p、miR-4763-3p、miR-4771、miR-4783-3p、miR-4783-5p、miR-4787-3p、miR-4792、miR-498、miR-5008-5p、miR-5010-5p、miR-504-3p、miR-5195-3p、miR-550a-5p、miR-5572、miR-5739、miR-6075、miR-6076、miR-6088、miR-6124、miR-6131、miR-6132、miR-614、miR-615-5p、miR-619-5p、miR-642b-3p、miR-6510-5p、miR-6511a-5p、miR-6515-3p、miR-6515-5p、miR-663b、miR-6716-5p、miR-6717-5p、miR-6722-3p、miR-6724-5p、miR-6726-5p、miR-6737-5p、miR-6741-5p、miR-6742-5p、miR-6743-5p、miR-6746-5p、miR-6749-5p、miR-6760-5p、miR-6762-5p、miR-6765-3p、miR-6765-5p、miR-6766-3p、miR-6766-5p、miR-6771-5p、miR-6774-5p、miR-6777-5p、miR-6778-5p、miR-6780b-5p、miR-6781-5p、miR-6782-5p、miR-6784-5p、miR-6785-5p、miR-6787-5p、miR-6789-5p、miR-6791-5p、miR-6794-5p、miR-6800-5p、miR-6802-5p、miR-6803-5p、miR-6812-5p、miR-6816-5p、miR-6819-5p、miR-6821-5p、miR-6826-5p、miR-6831-5p、miR-6836-3p、miR-6840-3p、miR-6842-5p、miR-6850-5p、miR-6861-5p、miR-6869-5p、miR-6870-5p、miR-6877-5p、miR-6879-5p、miR-6880-3p 、miR-6880-5p、miR-6885-5p、miR-6887-5p、miR-7107-5p、miR-7108-3p、miR-7109-5p、miR-711、miR-7113-3p、miR-7150、miR-744-5p、miR-7975、miR-7977、miR-8052、miR-8069、miR-8073、miR-887-3p、miR-937-5pで表される膀胱がん由来の遺伝子の発現量、並びに場合により、miR-1202、miR-1207-5p、miR-1246、miR-1254、miR-135a-3p、miR-1469、miR-149-3p、miR-150-3p、miR-1914-3p、miR-191-5p、miR-423-5p、miR-663a、miR-92a-2-5p、miR-92a-3p、miR-940で表される膀胱がん由来の遺伝子の発現量の1つ以上(例えば発現プロフィール)をin vitroで測定し、該測定された発現量(及び任意に同様に測定された健常者の対照発現量)を用いて被験体が膀胱がんに罹患しているか否かをin vitroで評価することを含む、膀胱がんの検出方法に関する。本方法において、例えば、膀胱がんの罹患が疑われる被験体と、膀胱がんに罹患していない被験者とから採取した血液、血清、血漿等の検体について、検体中の上記遺伝子の発現量と、膀胱がんに罹患していない被験者の対照発現量とを用いて、(例えば両発現量を比較して)、当該検体中の標的核酸の発現量に差がある場合、被験体が、膀胱がんに罹患していると評価することができる。
(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、当該被験体中の膀胱がん(細胞)の存在又は不存在を評価するステップ、
を含むことができる。
iR-6771-5pであり、miR-6774-5pがhsa-miR-6774-5pであり、miR-6777-5pがhsa-miR-6777-5pであり、miR-6778-5pがhsa-miR-6778-5pであり、miR-6780b-5pがhsa-miR-6780b-5pであり、miR-6781-5pがhsa-miR-6781-5pであり、miR-6782-5pがhsa-miR-6782-5pであり、miR-6784-5pがhsa-miR-6784-5pであり、miR-6785-5pがhsa-miR-6785-5pであり、miR-6787-5pがhsa-miR-6787-5pであり、miR-6789-5pがhsa-miR-6789-5pであり、miR-6791-5pがhsa-miR-6791-5pであり、miR-6794-5pがhsa-miR-6794-5pであり、miR-6800-5pがhsa-miR-6800-5pであり、miR-6802-5pがhsa-miR-6802-5pであり、miR-6803-5pがhsa-miR-6803-5pであり、miR-6812-5pがhsa-miR-6812-5pであり、miR-6816-5pがhsa-miR-6816-5pであり、miR-6819-5pがhsa-miR-6819-5pであり、miR-6821-5pがhsa-miR-6821-5pであり、miR-6826-5pがhsa-miR-6826-5pであり、miR-6831-5pがhsa-miR-6831-5pであり、miR-6836-3pがhsa-miR-6836-3pであり、miR-6840-3pがhsa-miR-6840-3pであり、miR-6842-5pがhsa-miR-6842-5pであり、miR-6850-5pがhsa-miR-6850-5pであり、miR-6861-5pがhsa-miR-6861-5pであり、miR-6869-5pがhsa-miR-6869-5pであり、miR-6870-5pがhsa-miR-6870-5pであり、miR-6877-5pがhsa-miR-6877-5pであり、miR-6879-5pがhsa-miR-6879-5pであり、miR-6880-3p がhsa-miR-6880-3p であり、miR-6880-5pがhsa-miR-6880-5pであり、miR-6885-5pがhsa-miR-6885-5pであり、miR-6887-5pがhsa-miR-6887-5pであり、miR-7107-5pがhsa-miR-7107-5pであり、miR-7108-3pがhsa-miR-7108-3pであり、miR-7109-5pがhsa-miR-7109-5pであり、miR-711がhsa-miR-711であり、miR-7113-3pがhsa-miR-7113-3pであり、miR-7150がhsa-miR-7150であり、miR-744-5pがhsa-miR-744-5pであり、miR-7975がhsa-miR-7975であり、miR-7977がhsa-miR-7977であり、miR-8052がhsa-miR-8052であり、miR-8069がhsa-miR-8069であり、miR-8073がhsa-miR-8073であり、miR-887-3pがhsa-miR-887-3pであり、miR-937-5pがhsa-miR-937-5pである。
(a)配列番号1~228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1~228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1~228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1~228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229~243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229~243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229~243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229~243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。
(a)被験体の検体から調製されたRNA(ここで、ステップ(b)の定量RT-PCRのために、例えばRNAの3’末端はポリアデニル化されていてもよい、又はいずれか若しくは両方の末端に任意の配列がライゲーション法などで付加されていてもよい)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、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によって測定するステップ、
(c)上記(b)の測定結果に基づいて、膀胱がん(又は膀胱がん由来の遺伝子)の存在又は不存在を評価するステップ、
を含むことができる。
(a)膀胱がん患者由来であること及び膀胱がんを含まない被験体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膀胱がんを含むこと又は膀胱がんを含まないことを決定又は評価する、或いは膀胱がん患者由来発現量を膀胱がんに罹患していない被験者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。ここで、式1~3、5及び6の式中のxは説明変数であり、上記2節に記載したポリヌクレオチド類から選択されるポリヌクレオチド又はその断片を測定することによって得られる値を含み、具体的には本発明の膀胱がん患者と膀胱がんに罹患していない被験者を判別するための説明変数は、例えば下記の(1)又は(2)より選択される遺伝子発現量である:
(1)配列番号1~228のいずれかで表される塩基配列又はその相補的配列において、15以上の連続した塩基を含むDNAのいずれかによって測定される膀胱がん患者及び膀胱がんに罹患していない被験者の血清における遺伝子発現量;又は
(2)配列番号229~243のいずれかで表される塩基配列又はその相補的配列において、15以上の連続した塩基を含むDNAのいずれかによって測定される膀胱がん患者及び膀胱がんに罹患していない被験者の血清における遺伝子発現量。
<検体の採取>
インフォームドコンセントを得た膀胱がん患者392人、肺がん患者50人、大腸がん患者50人、食道がん患者50人、胃がん患者50人、肝臓がん患者50人、胆道がん患者50人、膵臓がん患者50人、前立腺がん患者50人、乳がん患者50人、卵巣がん患者50人、子宮肉腫患者11人、悪性脳腫瘍患者50人、悪性骨軟部腫患者50人、良性骨軟部腫患者50人、乳良性疾患患者28人、良性卵巣腫瘍患者28人、前立腺良性疾患患者50人、子宮筋腫患者18人、良性脳腫瘍患者26人、健常者100人の合計1303人(表2)からベノジェクトII真空採血管VP-AS109K63(テルモ株式会社(日本))を用いてそれぞれ血清を採取した。
検体として上記の合計1303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))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。
検体として上記の合計1303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 21に登録されているmiRNAの中で、2,565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、欠損値はシグナル値0.1で置換した。その結果、上記の1303人の血清に対する、網羅的なmiRNAの遺伝子発現量を得た。
<miRNA1個又は2~5個の組合せによる膀胱がん判別分析>
本実施例では、膀胱がん患者と膀胱がんに罹患していない被験者を含む学習検体群(表4)を用いて、1個~5個の遺伝子マーカーによる判別式を作成した上で、検証検体群(表4)において判別性能を評価し、1~5個で判別性能上位の各50式、合計250式の判別式に用いられる遺伝子を抽出することで、膀胱がんを検出できる遺伝子マーカー149個を取得した(表6)。
上記の結果、遺伝子数1個で判別性能上位の各50式が得られた。この判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群及び検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表7-1に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。
上記の結果、遺伝子の組み合わせ数2個で判別性能上位の各50式が得られた。この判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群、検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表8-1~2に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。精度は84%~89%、膀胱がんを判別する感度は86%~96%と非常に高い判別性能を示した(表8-2)。遺伝子の組み合わせ数2個で判別を行うための判別式及び閾値を表8-3に表す。
上記の結果、遺伝子の組み合わせ数3個で判別性能上位の各50式が得られた。この判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群、検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表9-1~2に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。
上記の結果、遺伝子の組み合わせ数4個で判別性能上位の各50式が得られた。この判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群、検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表10-1~2に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。
上記の結果、遺伝子の組み合わせ数5個で判別性能上位の各50式が得られた。この判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群、検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表11-1~2に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。
<miRNA1個又は2個~104個の組合せによる膀胱がん判別分析>
本実施例では、膀胱がん患者を膀胱がん以外のがん患者、良性疾患患者、健常者を含む学習検体群(表4)を用いて、1個~104個の遺伝子マーカーによる判別式を作成した上で、検証検体群(表4)において判別性能を評価し、高い判別精度を示した104個までの遺伝子を組み合わせた判別式に用いられる遺伝子を抽出することで、膀胱がんを検出できる遺伝子マーカーを取得した(表12)。
上記の結果、遺伝子3個の組合せによる判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群、検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表13-1~2に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。
上記の結果、遺伝子10個の組合せによる判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群、検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表14-1に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。表14-2の判別式で表される判別式に測定値を入力してyを得、式9にyを代入して得た値を判別得点として検証検体群における病型別にプロットし、病型によらず膀胱がんと優位に分離することを図16に示した。図の縦軸は判別得点を示し、閾値0.5より大きい得点を膀胱がんに罹患している、小さい得点を膀胱がんに罹患していないと判別している。
上記の結果、遺伝子104個の組合せによる判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群、検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表15-1に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。
上記の結果、遺伝子1個又は2個から103個の組合せによる判別式とその閾値(陽陰性を判別する。閾値以上が陽性。)学習検体群、検証検体群における感度、特異度、精度、AUC及び判別式に使用した遺伝子を表16-1に示す。これらの判別式に含まれる遺伝子を、膀胱がん患者と膀胱がんに罹患していない被験者を判別可能な診断マーカーとして選択した。遺伝子1個又は2個から104個の組合せによる判別を行うための判別式及び閾値を表16-2に表す(遺伝子104個の組合せは、上記の通り表15-1に示されている)。
<膀胱がん患者と膀胱がん以外のがん患者、良性疾患患者、健常者における血清中miRNA発現量の比較>
本実施例では、膀胱がん患者を膀胱がん以外のがん患者、良性疾患患者、健常者における血清中miRNA発現量の比較を上記の参考例で遺伝子発現量を測定した学習検体群(表4)を用いて行った。具体的には、まず上記の参考例に示したとおり、陽性検体群として膀胱がん患者261人、陰性検体群として膀胱がん以外のがん患者408人、良性疾患患者133人及び健常者67人の学習検体群のmiRNA発現量を合わせてglobal normalizationで正規化した。次に、より信頼性の高い診断マーカーを評価するため、陽性検体群又は陰性検体群のいずれかの群において、50%以上の検体で2の6乗以上の遺伝子発現量を有する遺伝子のみを選択した。さらに、陽性検体群又は陰性検体群での遺伝子発現量について統計的有意差がある遺伝子を評価するため、等分散を仮定した両側t検定を行い、ボンフェローニ補正したP値を算出した。さらに、測定時のノイズの影響を受けやすさを評価するため、陽性検体群又は陰性検体群の対数変換した遺伝子発現量の差分(Fold change)の絶対値を算出した。補正後のP値が0.01以下かつFold changeの絶対値が0.5以上の遺伝子を発現変動遺伝子として抽出することで、膀胱がんを検出可能な診断マーカー89個を取得した(表17)。選択された遺伝子の陽性検体群と陰性検体群の発現量の平均値とSD、ボンフェローニ補正したP値とFold changeの絶対値を表17に示す。このうち、膀胱がんの有無を検査するマーカーとして新規に見出された遺伝子は、配列番号1、2、3、4、5、11、12、15、17、19、20、21、26、27、28、31、35、36、41、44、45、47、48、49、50、53、59、65、67、72、73、74、76、80、82、83、85、88、89、95、96、98、99、104、107、108、119、120、121、125、126、128、130、132、133、135、136、137、138、142、146、148、149、150、152、154、155、156、161、164、169、172、174、176、179、182、198、201、204、209、219、222、223、224、226に表される塩基配列からなるポリヌクレオチドである。
<TNM分類でT2以上の膀胱がん患者とT2未満の膀胱がん患者の判別分析>
本実施例では、TNM分類で原発腫瘍の壁内深達度を示すT分類で、治療法が膀胱全摘対象となるT2以上の患者と内視鏡やBCG注入療法などの治療対象となるT2未満患者を含む学習検体群(表5)を用いて、1個の遺伝子マーカーによる判別式を作成した上で、検証検体群(表5)において判別性能を評価し、下記の398個の遺伝子群から精度の高い上位14個に含まれる遺伝子を抽出し、T2以上の膀胱がんを検出できる遺伝子マーカーを取得した(表18)。
本実施例では、実施例1~3にそれぞれ示される膀胱がん患者と膀胱がんに罹患していない被験者を判別する遺伝子のうち、実施例1と2に共通する遺伝子を抽出し膀胱がんを検出できるより汎用性の高い遺伝子マーカー43個を取得した(表20)。また、実施例1と3に共通する遺伝子を抽出し膀胱がんを検出できるより汎用性の高い遺伝子マーカー62個を取得した(表21)。また、実施例2と3に共通する遺伝子を抽出し膀胱がんを検出できるより汎用性の高い遺伝子マーカー30個を取得した(表22)。また実施例1~3全てに共通する遺伝子を抽出し、膀胱がんを検出できるより汎用性の高い遺伝子マーカー23個を取得した(表23)。
表20~23に示される遺伝子は、様々な解析手法においても共通して使用できる汎用性の高い膀胱がんを検出できるマーカーであるといえる。
<他がんとの判別を目的とした膀胱がん判別分析>
本実施例では、膀胱がん患者392人、膀胱がん以外の各がん患者は、参考例に示したうち40人ずつとし、子宮肉腫患者群は0人、健常人は100人、計972人の血清に対する解析を行った。各検体群の1/2の検体を学習検体群に、残り1/2の検体を検証検体群に振り分けた(表24)。
Claims (18)
- 膀胱がんマーカーである、miR-6087、miR-1185-1-3p、miR-1185-2-3p、miR-1193、miR-1199-5p、miR-1225-5p、miR-1227-5p、miR-1228-3p、miR-1228-5p、miR-1237-5p、miR-1238-5p、miR-1247-3p、miR-1268a、miR-1268b、miR-1273g-3p、miR-128-2-5p、miR-1343-3p、miR-1343-5p、miR-1470、miR-17-3p、miR-187-5p、miR-1908-3p、miR-1908-5p、miR-1909-3p、miR-1915-3p、miR-210-5p、miR-24-3p、miR-2467-3p、miR-2861、miR-296-3p、miR-29b-3p、miR-3131、miR-3154、miR-3158-5p、miR-3160-5p、miR-3162-5p、miR-3178、miR-3180-3p、miR-3184-5p、miR-3185、miR-3194-3p、miR-3195、miR-3197、miR-320a、miR-320b、miR-328-5p、miR-342-5p、miR-345-3p、miR-3616-3p、miR-3619-3p、miR-3620-5p、miR-3621、miR-3622a-5p、miR-3648、miR-3652、miR-3656、miR-3663-3p、miR-3679-5p、miR-371b-5p、miR-373-5p、miR-3917、miR-3940-5p、miR-3960、miR-4258、miR-4259、miR-4270、miR-4286、miR-4298、miR-4322、miR-4327、miR-4417、miR-4419b、miR-4429、miR-4430、miR-4433a-3p、miR-4436b-5p、miR-4443、miR-4446-3p、miR-4447、miR-4448、miR-4449、miR-4454、miR-4455、miR-4459、miR-4462、miR-4466、miR-4467、miR-4480、miR-4483、miR-4484、miR-4485-5p、miR-4488、miR-4492、miR-4505、miR-4515、miR-4525、miR-4534、miR-4535、miR-4633-3p、miR-4634、miR-4640-5p、miR-4649-5p、miR-4651、miR-4652-5p、miR-4655-5p、miR-4656、miR-4658、miR-4663、miR-4673、miR-4675、miR-4687-3p、miR-4687-5p、miR-4690-5p、miR-4695-5p、miR-4697-5p、miR-4706、miR-4707-3p、miR-4707-5p、miR-4708-3p、miR-4710、miR-4718、miR-4722-5p、miR-4725-3p、miR-4726-5p、miR-4727-3p、miR-4728-5p、miR-4731-5p、miR-4736、miR-4739、miR-4740-5p、miR-4741、miR-4750-5p、miR-4755-3p、miR-4763-3p、miR-4771、miR-4783-3p、miR-4783-5p、miR-4787-3p、miR-4792、miR-498、miR-5008-5p、miR-5010-5p、miR-504-3p、miR-5195-3p、miR-550a-5p、miR-5572、miR-5739、miR-6075、miR-6076、miR-6088、miR-6124、miR-6131、miR-6132、miR-614、miR-615-5p、miR-619-5p、miR-642b-3p、miR-6510-5p、miR-6511a-5p、miR-6515-3p、miR-6515-5p、miR-663b、miR-6716-5p、miR-6717-5p、miR-6722-3p、miR-6724-5p、miR-6726-5p、miR-6737-5p、miR-6741-5p、miR-6742-5p、miR-6743-5p、miR-6746-5p、miR-6749-5p、miR-6760-5p、miR-6762-5p、miR-6765-3p、miR-6765-5p、miR-6766-3p、miR-6766-5p、miR-6771-5p、miR-6774-5p、miR-6777-5p、miR-6778-5p、miR-6780b-5p、miR-6781-5p、miR-6782-5p、miR-6784-5p、miR-6785-5p、miR-6787-5p、miR-6789-5p、miR-6791-5p、miR-6794-5p、miR-6800-5p、miR-6802-5p、miR-6803-5p、miR-6812-5p、miR-6816-5p、miR-6819-5p、miR-6821-5p、miR-6826-5p、miR-6831-5p、miR-6836-3p、miR-6840-3p、miR-6842-5p、miR-6850-5p、miR-6861-5p、miR-6869-5p、miR-6870-5p、miR-6877-5p、miR-6879-5p、miR-6880-3p、miR-6880-5p、miR-6885-5p、miR-6887-5p、miR-7107-5p、miR-7108-3p、miR-7109-5p、miR-711、miR-7113-3p、miR-7150、miR-744-5p、miR-7975、miR-7977、miR-8052、miR-8069、miR-8073、miR-887-3p、miR-937-5pから選択される少なくとも1つのポリヌクレオチド、又は該ポリヌクレオチドの相補鎖と特異的に結合可能な核酸を含む、膀胱がんの検出用キット。
- 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1~228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1~228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1~228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1~228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に記載のキット。 - 前記キットが、別の膀胱がんマーカーである、miR-1202、miR-1207-5p、miR-1246、miR-1254、miR-135a-3p、miR-1469、miR-149-3p、miR-150-3p、miR-1914-3p、miR-191-5p、miR-423-5p、miR-663a、miR-92a-2-5p、miR-92a-3p、miR-940から選択される少なくとも1つのポリヌクレオチド、又は該ポリヌクレオチドの相補鎖と特異的に結合可能な核酸をさらに含む、請求項1又は2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229~243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229~243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229~243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229~243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3に記載のキット。 - 膀胱がんマーカーである、miR-6087、miR-1185-1-3p、miR-1185-2-3p、miR-1193、miR-1199-5p、miR-1225-5p、miR-1227-5p、miR-1228-3p、miR-1228-5p、miR-1237-5p、miR-1238-5p、miR-1247-3p、miR-1268a、miR-1268b、miR-1273g-3p、miR-128-2-5p、miR-1343-3p、miR-1343-5p、miR-1470、miR-17-3p、miR-187-5p、miR-1908-3p、miR-1908-5p、miR-1909-3p、miR-1915-3p、miR-210-5p、miR-24-3p、miR-2467-3p、miR-2861、miR-296-3p、miR-29b-3p、miR-3131、miR-3154、miR-3158-5p、miR-3160-5p、miR-3162-5p、miR-3178、miR-3180-3p、miR-3184-5p、miR-3185、miR-3194-3p、miR-3195、miR-3197、miR-320a、miR-320b、miR-328-5p、miR-342-5p、miR-345-3p、miR-3616-3p、miR-3619-3p、miR-3620-5p、miR-3621、miR-3622a-5p、miR-3648、miR-3652、miR-3656、miR-3663-3p、miR-3679-5p、miR-371b-5p、miR-373-5p、miR-3917、miR-3940-5p、miR-3960、miR-4258、miR-4259、miR-4270、miR-4286、miR-4298、miR-4322、miR-4327、miR-4417、miR-4419b、miR-4429、miR-4430、miR-4433a-3p、miR-4436b-5p、miR-4443、miR-4446-3p、miR-4447、miR-4448、miR-4449、miR-4454、miR-4455、miR-4459、miR-4462、miR-4466、miR-4467、miR-4480、miR-4483、miR-4484、miR-4485-5p、miR-4488、miR-4492、miR-4505、miR-4515、miR-4525、miR-4534、miR-4535、miR-4633-3p、miR-4634、miR-4640-5p、miR-4649-5p、miR-4651、miR-4652-5p、miR-4655-5p、miR-4656、miR-4658、miR-4663、miR-4673、miR-4675、miR-4687-3p、miR-4687-5p、miR-4690-5p、miR-4695-5p、miR-4697-5p、miR-4706、miR-4707-3p、miR-4707-5p、miR-4708-3p、miR-4710、miR-4718、miR-4722-5p、miR-4725-3p、miR-4726-5p、miR-4727-3p、miR-4728-5p、miR-4731-5p、miR-4736、miR-4739、miR-4740-5p、miR-4741、miR-4750-5p、miR-4755-3p、miR-4763-3p、miR-4771、miR-4783-3p、miR-4783-5p、miR-4787-3p、miR-4792、miR-498、miR-5008-5p、miR-5010-5p、miR-504-3p、miR-5195-3p、miR-550a-5p、miR-5572、miR-5739、miR-6075、miR-6076、miR-6088、miR-6124、miR-6131、miR-6132、miR-614、miR-615-5p、miR-619-5p、miR-642b-3p、miR-6510-5p、miR-6511a-5p、miR-6515-3p、miR-6515-5p、miR-663b、miR-6716-5p、miR-6717-5p、miR-6722-3p、miR-6724-5p、miR-6726-5p、miR-6737-5p、miR-6741-5p、miR-6742-5p、miR-6743-5p、miR-6746-5p、miR-6749-5p、miR-6760-5p、miR-6762-5p、miR-6765-3p、miR-6765-5p、miR-6766-3p、miR-6766-5p、miR-6771-5p、miR-6774-5p、miR-6777-5p、miR-6778-5p、miR-6780b-5p、miR-6781-5p、miR-6782-5p、miR-6784-5p、miR-6785-5p、miR-6787-5p、miR-6789-5p、miR-6791-5p、miR-6794-5p、miR-6800-5p、miR-6802-5p、miR-6803-5p、miR-6812-5p、miR-6816-5p、miR-6819-5p、miR-6821-5p、miR-6826-5p、miR-6831-5p、miR-6836-3p、miR-6840-3p、miR-6842-5p、miR-6850-5p、miR-6861-5p、miR-6869-5p、miR-6870-5p、miR-6877-5p、miR-6879-5p、miR-6880-3p、miR-6880-5p、miR-6885-5p、miR-6887-5p、miR-7107-5p、miR-7108-3p、miR-7109-5p、miR-711、miR-7113-3p、miR-7150、miR-744-5p、miR-7975、miR-7977、miR-8052、miR-8069、miR-8073、miR-887-3p、miR-937-5pから選択される少なくとも1つのポリヌクレオチド、又は該ポリヌクレオチドの相補鎖と特異的に結合可能な核酸を含む、膀胱がんの検出用デバイス。
- 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1~228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1~228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1~228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1~228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5に記載のデバイス。 - 前記デバイスが、別の膀胱がんマーカーである、miR-1202、miR-1207-5p、miR-1246、miR-1254、miR-135a-3p、miR-1469、miR-149-3p、miR-150-3p、miR-1914-3p、miR-191-5p、miR-423-5p、miR-663a、miR-92a-2-5p、miR-92a-3p、miR-940から選択される少なくとも1つのポリヌクレオチド、又は該ポリヌクレオチドの相補鎖と特異的に結合可能な核酸をさらに含む、請求項5又は6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229~243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229~243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229~243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229~243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7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5~8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9に記載のデバイス。
- 被験体の検体において、膀胱がんマーカーである、miR-6087、miR-1185-1-3p、miR-1185-2-3p、miR-1193、miR-1199-5p、miR-1225-5p、miR-1227-5p、miR-1228-3p、miR-1228-5p、miR-1237-5p、miR-1238-5p、miR-1247-3p、miR-1268a、miR-1268b、miR-1273g-3p、miR-128-2-5p、miR-1343-3p、miR-1343-5p、miR-1470、miR-17-3p、miR-187-5p、miR-1908-3p、miR-1908-5p、miR-1909-3p、miR-1915-3p、miR-210-5p、miR-24-3p、miR-2467-3p、miR-2861、miR-296-3p、miR-29b-3p、miR-3131、miR-3154、miR-3158-5p、miR-3160-5p、miR-3162-5p、miR-3178、miR-3180-3p、miR-3184-5p、miR-3185、miR-3194-3p、miR-3195、miR-3197、miR-320a、miR-320b、miR-328-5p、miR-342-5p、miR-345-3p、miR-3616-3p、miR-3619-3p、miR-3620-5p、miR-3621、miR-3622a-5p、miR-3648、miR-3652、miR-3656、miR-3663-3p、miR-3679-5p、miR-371b-5p、miR-373-5p、miR-3917、miR-3940-5p、miR-3960、miR-4258、miR-4259、miR-4270、miR-4286、miR-4298、miR-4322、miR-4327、miR-4417、miR-4419b、miR-4429、miR-4430、miR-4433a-3p、miR-4436b-5p、miR-4443、miR-4446-3p、miR-4447、miR-4448、miR-4449、miR-4454、miR-4455、miR-4459、miR-4462、miR-4466、miR-4467、miR-4480、miR-4483、miR-4484、miR-4485-5p、miR-4488、miR-4492、miR-4505、miR-4515、miR-4525、miR-4534、miR-4535、miR-4633-3p、miR-4634、miR-4640-5p、miR-4649-5p、miR-4651、miR-4652-5p、miR-4655-5p、miR-4656、miR-4658、miR-4663、miR-4673、miR-4675、miR-4687-3p、miR-4687-5p、miR-4690-5p、miR-4695-5p、miR-4697-5p、miR-4706、miR-4707-3p、miR-4707-5p、miR-4708-3p、miR-4710、miR-4718、miR-4722-5p、miR-4725-3p、miR-4726-5p、miR-4727-3p、miR-4728-5p、miR-4731-5p、miR-4736、miR-4739、miR-4740-5p、miR-4741、miR-4750-5p、miR-4755-3p、miR-4763-3p、miR-4771、miR-4783-3p、miR-4783-5p、miR-4787-3p、miR-4792、miR-498、miR-5008-5p、miR-5010-5p、miR-504-3p、miR-5195-3p、miR-550a-5p、miR-5572、miR-5739、miR-6075、miR-6076、miR-6088、miR-6124、miR-6131、miR-6132、miR-614、miR-615-5p、miR-619-5p、miR-642b-3p、miR-6510-5p、miR-6511a-5p、miR-6515-3p、miR-6515-5p、miR-663b、miR-6716-5p、miR-6717-5p、miR-6722-3p、miR-6724-5p、miR-6726-5p、miR-6737-5p、miR-6741-5p、miR-6742-5p、miR-6743-5p、miR-6746-5p、miR-6749-5p、miR-6760-5p、miR-6762-5p、miR-6765-3p、miR-6765-5p、miR-6766-3p、miR-6766-5p、miR-6771-5p、miR-6774-5p、miR-6777-5p、miR-6778-5p、miR-6780b-5p、miR-6781-5p、miR-6782-5p、miR-6784-5p、miR-6785-5p、miR-6787-5p、miR-6789-5p、miR-6791-5p、miR-6794-5p、miR-6800-5p、miR-6802-5p、miR-6803-5p、miR-6812-5p、miR-6816-5p、miR-6819-5p、miR-6821-5p、miR-6826-5p、miR-6831-5p、miR-6836-3p、miR-6840-3p、miR-6842-5p、miR-6850-5p、miR-6861-5p、miR-6869-5p、miR-6870-5p、miR-6877-5p、miR-6879-5p、miR-6880-3p、miR-6880-5p、miR-6885-5p、miR-6887-5p、miR-7107-5p、miR-7108-3p、miR-7109-5p、miR-711、miR-7113-3p、miR-7150、miR-744-5p、miR-7975、miR-7977、miR-8052、miR-8069、miR-8073、miR-887-3p、miR-937-5pから選択される少なくとも1つのポリヌクレオチドの発現量を測定し、該測定された発現量を用いて被験体が膀胱がんに罹患しているか否かをin vitroで評価することを含む、膀胱がんの検出方法。
- 膀胱がん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膀胱がんに罹患していない被験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、かつ膀胱がんの存在又は不存在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前記少なくとも1つのポリヌクレオチドの発現量を代入し、それによって、膀胱がんの存在又は不存在を評価することを含む、請求項11に記載の方法。
- 前記ポリヌクレオチド又は該ポリヌクレオチドの相補鎖と特異的に結合可能な核酸を用いて前記ポリヌクレオチドの発現量の測定を行い、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1~228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1~228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1~228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1~228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11又は12に記載の方法。 - 別の膀胱がんマーカーである、miR-1202、miR-1207-5p、miR-1246、miR-1254、miR-135a-3p、miR-1469、miR-149-3p、miR-150-3p、miR-1914-3p、miR-191-5p、miR-423-5p、miR-663a、miR-92a-2-5p、miR-92a-3p、miR-940から選択される少なくとも1つのポリヌクレオチドの発現量を測定することをさらに含む、請求項11~13のいずれか1項に記載の方法。
- 前記ポリヌクレオチド又は該ポリヌクレオチドの相補鎖と特異的に結合可能な核酸を用いて前記ポリヌクレオチドの発現量の測定を行い、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229~243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229~243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229~243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229~243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14に記載の方法。 - 前記ポリヌクレオチド又は該ポリヌクレオチドの相補鎖と特異的に結合可能な核酸を含む、請求項1~4のいずれか1項に記載のキット又は請求項5~10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する、請求項11~15のいずれか1項に記載の方法。
- 前記被験体が、ヒトである、請求項11~16のいずれか1項に記載の方法。
- 前記検体が、血液、血清又は血漿である、請求項11~17のいずれか1項に記載の方法。
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WO2021153789A1 (ja) * | 2020-01-30 | 2021-08-05 | 学校法人福岡大学 | 子宮内感染の検出方法 |
WO2023013568A1 (ja) * | 2021-08-02 | 2023-02-09 | 株式会社メディカル・アーク | イヌの癌の診断方法 |
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