WO2006062118A1 - Nouveaux marqueurs pour le pronostic predictif du carcinome papillaire de la thyroide - Google Patents

Nouveaux marqueurs pour le pronostic predictif du carcinome papillaire de la thyroide Download PDF

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WO2006062118A1
WO2006062118A1 PCT/JP2005/022436 JP2005022436W WO2006062118A1 WO 2006062118 A1 WO2006062118 A1 WO 2006062118A1 JP 2005022436 W JP2005022436 W JP 2005022436W WO 2006062118 A1 WO2006062118 A1 WO 2006062118A1
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gene
marker
prognosis
thyroid cancer
papillary thyroid
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PCT/JP2005/022436
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English (en)
Japanese (ja)
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Yukiko Nakata
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Kansai Technology Licensing Organization Co., Ltd.
Osaka University
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Publication of WO2006062118A1 publication Critical patent/WO2006062118A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/78—Thyroid gland hormones, e.g. T3, T4, TBH, TBG or their receptors

Definitions

  • the present invention relates to markers such as genetic markers, mRNA markers, and protein markers for diagnosing or predicting malignancy, risk, or prognosis of papillary thyroid cancer.
  • the present invention also relates to an antibody against the protein marker, a method for diagnosing or predicting malignancy, risk or prognosis of papillary thyroid cancer, and a DNAZRNA chip for measuring the marker.
  • the present invention relates to a kit for diagnosing or predicting malignancy, risk or prognosis of papillary thyroid cancer.
  • the number of patients with thyroid cancer is said to be 10,000 in Japan every year According to the American Cancer Society, the number of new thyroid cancer patients in the United States in 2005 was 25,690 Similarly, there are 3100 (2005) new cases per year in Canada and 1431 new thyroid cancer cases in 2001 in the UK.
  • papillary cancer There are five types of thyroid cancer: papillary cancer, follicular cancer, medullary cancer, undifferentiated cancer, and malignant lymphoma.
  • papillary cancer accounts for 85-90% of thyroid cancer.
  • papillary thyroid cancer rarely causes cancer death with a good prognosis.
  • about 10% of cases of papillary thyroid cancer have a poor prognosis, and distant metastases such as lung, brain, and bone also lead to cancer death.
  • papillary thyroid cancer is said to be classified into a low-risk group with good prognosis and a high-risk group with poor prognosis.
  • Cancer mortality classification for papillary thyroid cancer is performed at the time of surgery based on the size of the primary lesion, age, presence / absence of metastasis, presence / absence of cancer invasion outside the thyroid, etc.
  • m I whole body scintigraphy with CT scan is very useful for diagnosing the presence or absence of papillary thyroid cancer, especially the progress of metastasis and recurrence after surgery. Since scan uses radiation, it has a drawback that frequent inspections cannot avoid affecting the living body.
  • Patent document 1 describes a thyroid tumor marker, but this marker is insufficient as a tumor marker for papillary thyroid cancer.
  • Patent Document 1 Japanese Unexamined Patent Application Publication No. 2004-283074
  • an object of the present invention is to provide markers such as genetic markers, mRNA markers, and protein markers for diagnosing or predicting malignancy, risk, or prognosis of papillary thyroid cancer.
  • Another object of the present invention is to provide an antibody against the protein marker, a method for diagnosing or predicting malignancy, risk or prognosis of papillary thyroid cancer, and a DNAZ RNA chip for measuring the marker. To do.
  • an object of the present invention is to provide a kit for diagnosing or predicting malignancy, risk or prognosis of papillary thyroid cancer. Means for solving the problem
  • the inventor classified papillary thyroid cancer patients into a low-risk group and a high-risk group according to age, distant metastasis, and presence / absence of invasion.
  • the present inventor found that the high-risk group (Group A: elderly patients 51 years of age or older who had cancer metastasis invasion outside the thyroid by pathological findings) and the low-risk group (Group C) : A young patient under 30 years old who suffered from localized thyroid gland due to pathological findings) and compared the gene expression levels in the tissues of the primary lesion of papillary thyroid cancer in detail, and conducted extensive studies As a result, it was found that the expression levels of 11 genes are significantly different.
  • the present invention relates to the invention shown in the following items:
  • a marker for predicting the prognosis of papillary thyroid cancer consisting of a transcription or translation product thereof.
  • SUV39H2, CRLF1, TMPRSS2, FXYD3, MYCN, NMU, TREX1, KCNV1, CAP N6, PAPPA and SLC7A5 At least one gene selected from the group consisting of transcription or translation products The described marker.
  • the marker according to item 1 comprising at least one gene selected from the group consisting of KCNV1, PAPPA and SLC7A5 (hLATl), or a transcription or translation product thereof.
  • the marker consists of mRNA which is a transcription product of the gene, Ma 1 ⁇ force according to claim 1 ' ⁇ .
  • a method for predicting the prognosis of papillary thyroid cancer comprising quantifying the transcription product or translation product of the gene according to item 1.
  • a method for predicting prognosis of papillary thyroid cancer comprising a step of quantifying thyroglobulin and a step of quantifying a translation product of the gene according to item 1.
  • a kit for quantifying the protein according to Item 5 comprising a primary antibody against the protein according to Item 5 and a labeled secondary antibody against the primary antibody.
  • the malignancy, risk or prognosis of papillary thyroid cancer which is the most frequent among thyroid cancers, can be diagnosed or predicted. It can be performed.
  • the prognosis is predicted to be poor, and after surgery, the primary papillary cancer tissue is removed by surgery, and recurrence or metastasis takes place every 6 months to 1 year. It is possible to prevent cancer death by conducting a precise examination in consideration.
  • the size of the primary tumor is less than 1 cm, the size of the cancer is regularly monitored for increase, and even if surgery is performed Subsequent examinations can be omitted once every 2-3 years, eliminating unnecessary examinations, and by performing frequent CT scans and whole body scintigraphy to examine whether there is recurrence or metastasis. Medical exposure can be kept to a minimum.
  • the genetic markers for predicting the prognosis of papillary thyroid cancer of the present invention include the following genes, and these genetic markers are used alone or in combination of two or more types of markers. In combination, it can predict the prognosis of papillary thyroid cancer:
  • hLATl and SLC7A5 have different gene names and GenBank accession numbers! It is an amino acid transporter gene that has a common salt and a common salt.
  • the gene marker of the present invention is more preferably KCNV1, PAPPA and SLC7A5 (hLA
  • Power is a group power that is chosen.
  • the gene marker for predicting the prognosis of papillary thyroid cancer of the present invention includes the following genes, and these gene markers are used alone or in two kinds: Combining these markers can predict the prognosis of papillary thyroid cancer:
  • the base sequence of the gene marker of the present invention can be confirmed by searching a corresponding database accession number (Accession Number) described in Table I in a known database (NCBI).
  • the mRNA marker for predicting the prognosis of papillary thyroid cancer of the present invention also comprises at least one mRNA force expressed by the gene marker gene of the present invention.
  • the protein marker for predicting the prognosis of papillary thyroid cancer of the present invention is the present invention. At least one protein expressed by the gene marker gene.
  • the gene marker, mRNA marker and protein marker for predicting the prognosis of papillary thyroid cancer of the present invention may be simply referred to as a tumor marker.
  • “predicting the prognosis of papillary thyroid cancer” includes diagnosing the malignancy of thyroid cancer before surgery, predicting the course of postoperative papillary thyroid cancer, and the like.
  • Papillary thyroid cancer is a slow-growing cancer that requires complete removal of the cancer tissue by surgery. Therefore, by knowing the possibility of metastasis before surgery, it is possible to determine an appropriate policy for the type and frequency of post-surgery examinations. For example, by measuring the tumor marker of papillary thyroid cancer of the present invention, it becomes possible to predict the progress of 5 to 10 years after the operation in advance. As a result, it is possible to sufficiently care for a high-grade patient as much as possible to reduce the burden on the low-grade patient.
  • the method for predicting the prognosis of papillary thyroid cancer of the present invention is characterized by quantifying at least one mRNA expressed by a gene of the gene marker of the present invention.
  • specimens for quantifying mRNA include primary lesion surgical specimens, leukocytes in blood, and the like.
  • the method for predicting prognosis of papillary thyroid cancer of the present invention comprises quantifying at least one protein expressed by a gene of the gene marker of the present invention.
  • the protein can be quantified by, for example, HPLC, gel electrophoresis, isoelectric focusing, antigen-antibody reaction and the like.
  • the ELISA method is particularly preferred as an antigen-antibody reaction.
  • thyroglobulin has been used to predict the prognosis of papillary thyroid cancer metastasis. Thyroglobulin was thought to decrease in measured values due to surgery for papillary thyroid cancer and then to increase when metastasis occurred, but its accuracy was not satisfactory.
  • the risk diagnosis of papillary thyroid cancer using the gene marker of the present invention is, for example, in the thyroid tissue, blood or urine (preferably in the blood) of the normal control group with the infomed'concentration. Based on the amount of the tumor marker of the present invention, it can be carried out by comparing this standard with the amount of the tumor marker of the present invention in papillary thyroid cancer tissue, blood or urine (preferably in blood).
  • the quantification of the tumor marker is, for example, absolute per cell in the case of mRNA. It may be measured as a relative amount or as a relative amount. In the case of protein, it can be measured as the concentration in a sample such as blood. It is preferable to measure the mRNA gene expression level as a relative amount from the viewpoint that the measurement operation is simple and accurate.
  • the relative amount can be determined, for example, by setting a gene as an internal control and using the gene expression level.
  • the gene serving as the internal control is not particularly limited as long as it is a gene expressed in normal thyroid tissue cells and thyroid tumor cells, but for example, ⁇ -cuttin (GenBank Ac No. X00351) gene, GAPDH gene, etc.
  • a housekeeping gene is preferably exemplified.
  • the tumor marker is a protein, it can be preferably measured by an immunoassay such as ELISA using an antibody (monoclonal antibody, polyclonal antibody, particularly monoclonal antibody) against the protein.
  • the method for quantifying the mRNA marker is not particularly limited as long as it can quantitate the amount of specific mRNA in the cell.
  • the mRNA of the mRNA marker or the base sequence of the cDNA or Examples thereof include a method using a primer or probe that is an oligonucleotide that also serves as a partial force of the complementary base sequence and contains an oligonucleotide that binds site-specifically to the mRNA or cDNA of the mRNA marker.
  • the primers and probes described above have various modifications for detecting and quantifying the mRNA if the oligonucleotide forms site-specific base pairs with the mRNA of the marker mRNA or its cDNA. It may be.
  • a simple method with a small amount of required sample and a high accuracy and sensitivity is preferable.
  • a real-time PCR method, a competitive PCR method, a method for directly measuring mRNA, etc. can be given.
  • the same tube or well More preferred is a method in which the mRNA of the gene marker of the present invention and the mRNA of the internal control gene can be measured simultaneously by the above reaction.
  • cDNA is synthesized from intracellular total RNA or mRNA using reverse transcriptase, and the target region is amplified by PCR using this cDNA as a cage, and a reagent for real-time monitoring.
  • the real-time monitoring reagent include SYBR (registered trademark: MolecularProbes) Greenl, TaqMan (registered trademark: Applied Biosystems) probe, and the like.
  • the competitive PCR method includes, for example, a method of synthesizing cDNA from intracellular total RNA or mRNA using reverse transcriptase, and reacting this cDNA with a DNA competitor in the same tube, Further, there may be mentioned a method in which an RNA competitor is added together with mRNA during the reverse transcription reaction. Further, the internal sequence other than the competitor primer sequence may be, for example, a sequence homologous to the sequence of the mRNA for amplification or a non-homologous sequence.
  • examples of the method for directly measuring the mRNA include Invader (registered trademark: ThirdWave Technologies) RNA assembly.
  • the marker gene mRNA quantification method for predicting the prognosis of papillary thyroid cancer using the gene marker of the present invention is not limited to these methods, and the oligonucleotide, primer or probe is used. Various quantification methods used can be applied.
  • any method for quantifying the protein marker for quantifying the genetic marker for predicting the prognosis of papillary thyroid cancer of the present invention any method can be used as long as it can quantitate a specific protein in a cell.
  • a method using an antibody specific for the protein of the protein marker can be mentioned, and among them, a simple method with a small amount of necessary cells and a high accuracy and sensitivity is preferable.
  • Specific examples include various enzyme immunoassays (EIA) and radio immunoassays (RIA).
  • EIA enzyme immunoassays
  • RIA radio immunoassays
  • the enzyme-linked immunosorbent assay (ELISA) is used because it is more sensitive and simple.
  • Sandwich ELISA are preferred.
  • the antibody used in these methods may be a monoclonal antibody or a polyclonal antibody, depending on the protein quantification method. .
  • the protein marker quantification method for diagnosis of papillary thyroid cancer of the present invention is not limited to these methods.
  • the antibody of the present invention is, for example, an antibody produced by immunizing a mouse with a protein expressed by the gene marker gene of the present invention, an antibody produced from a hybridoma, particularly a monoclonal antibody.
  • An antibody is mentioned.
  • the animal used for immunization is particularly preferably a mouse, such as mice, rats, rabbits, goats and the like.
  • Induction of immunity can usually be performed by dividing the immunogen in an amount of lng to 10 mg into 1 to 5 times over 10 to 14 days. After sufficient immunization, organs capable of producing antibodies (spleen and lymph nodes) are aseptically removed from the animal and used as the parent strain at the time of cell fusion. The spleen is most preferable as an organ to be removed.
  • Myeloma cells are used as cell fusion partners. Myeloma cells are derived from mice
  • Rat origin human origin, etc., preferably mouse origin.
  • cell fusion include methods using polyethylene glycol, cell electrofusion, and the like, but methods using polyethylene glycol are simple and preferred.
  • Selection of spleen cells, myeloma cells, and hybridomas that did not undergo cell fusion can be performed, for example, by culturing in a serum medium supplemented with HAT supplement (hypoxanthine monoaminopterin-thymidine).
  • HAT supplement hyperxanthine monoaminopterin-thymidine
  • the selection of the hyperidoma is preferably direct ELISA on an EIA plate in which the above-mentioned culture supernatant is collected and the protein expressed by the gene marker gene of the present invention is immobilized.
  • the hybridoma corresponding to the strongly colored culture supernatant is selected as a hybridoma that produces an antibody that reacts with the protein expressed by the gene marker gene of the present invention.
  • Cloning is an operation for selecting and unifying antibody-producing hyperpridoma.
  • There are a limiting dilution method, a fibrin gel method, a method using a cell sorter, etc. but the limiting dilution method is preferred.
  • a hybridoma that produces the desired monoclonal antibody can be obtained.
  • Monoclonal antibodies can be obtained.
  • in order to obtain a large amount of monoclonal antibodies there are in vivo and in vitro methods, but in vivo methods are preferred, particularly in mouse ascites.
  • Purification of monoclonal antibodies from the culture supernatant and mouse ascites is performed by ammonium sulfate salt folding, affinity chromatography, ion exchange chromatography, hydroxyapatite column chromatography, etc. Considering simplicity, affinity chromatography is the most preferred. In order to obtain a higher purity monoclonal antibody, it is preferable to perform gel filtration chromatography or ion exchange chromatography as final purification after affinity chromatography. In order to use purified monoclonal antibodies for sandwich ELISA, antibody combinations must be determined. A sandwich ELISA can measure a small amount of antigen by sandwiching the antigen between two different antibodies, but each antibody preferably reacts with a different epitope.
  • a part of the purified monoclonal antibody is immobilized on an EIA plate and a part thereof is labeled with piotin or the like.
  • the labeling is not necessarily performed. Not necessary.
  • a serially diluted protein expressed by the gene marker gene of the present invention is added to an EIA plate on which an antibody is immobilized, and an antibody labeled or not labeled is added to examine the combination.
  • the DNAZRNA chip of the present invention comprises DNAZRNA capable of hybridizing with mRNA expressed by the gene marker gene of the present invention.
  • the kit of the present invention includes a primary antibody against a protein expressed by the gene marker gene of the present invention, and a labeled secondary antibody against the primary antibody.
  • the kit used for quantifying the mRNA marker for predicting the prognosis of papillary thyroid cancer using the gene marker of the present invention is for amplifying the cDNA of the mRNA marker in a quantifiable manner.
  • a specific mRNA in a cell comprising the primer and polymerase, and the probe to be paired with the amplification product for detection.
  • Other consumable reagents included in the kit of the present invention are not particularly limited. Examples include enzymes, knockers, reaction reagents, and (d) NTP mixes necessary for quantifying mRNA.
  • kits used for quantifying a protein marker for predicting prognosis of papillary thyroid cancer using the gene marker of the present invention comprises a first antibody specific for the protein of the protein marker, A kit for quantifying a specific protein in a cell containing a second antibody specific to the first antibody, for example, an antibody labeled with an appropriate enzyme or chemical substance.
  • Other consumable reagents contained in the kit of the present invention are not particularly limited, and examples thereof include enzymes, buffers, reaction reagents and the like necessary for quantifying proteins.
  • the DNAZRNA chip used for quantifying the mRNA level for the determination of papillary thyroid cancer using the gene marker of the present invention is the nucleotide sequence of the mRNA of the mRNA marker or its cDNA or the This is a DNAZRNA chip equipped with an oligo DNAZRNA that also serves as part of the complementary base sequence.
  • the DNAZRNA chip used for quantifying the mRNA marker for the determination of papillary thyroid cancer using the gene marker of the present invention the mRNA of the mRNA marker or its nucleotide sequence or its complementary nucleotide sequence This is a DNAZRNA chip with oligo DNAZRNA.
  • TPC thyroid papillary carcinoma
  • Total RNA was obtained from the method of Chmczynski and Sacchi (Single-Step Methods of RNA Isolation by Acid Guanidinium Thyocyanate-Phenol— Cnloroform Extraction. Chomczy nski P and Sacchi N. Anal. Biochem. 162: 156-159, 1987. ) And purified using RN easy Mini kit (Qiagen, Valencia, CA).
  • cRNA is prepared from 10 ⁇ g of total RNA, hybridized to HG-U133A Gene chip, Affimetrix oligonucleotide arrays (containing over 20,000 human genes), scanned, and analyzed according to the Aifymetrix (Santa Clara, CA) protocol did. Scanned image files were visually inspected for artifacts and standardized using GCOS software (Affimetrix). The fold change values, which show relative changes in gene expression levels, between young and old TPC tumors are compared and expressed differently between these two conditions by using the GCOS software (Affimetrix). Identified genes
  • a gene group with a different expression between two groups of papillary cancer that is considered to have a good prognosis and a papillary cancer that is thought to have a poor prognosis is known 20,000 genes Elected the middle power.
  • the j8 actin gene was used as an endgenous control.
  • the top 95 genes were selected from genes with significantly different expression levels that had a gene expression relative ratio of 2.0 or more between the two groups.
  • the results are shown in Table II below.
  • the 95 genes listed in Table II have a relative gene expression ratio between the two groups of 3.6 or more, and may be useful as genetic markers for predicting the prognosis of papillary thyroid cancer.
  • secondary screening was performed using these 95 genes.
  • Tissue samples and RNA were prepared and cDNA was synthesized in the same manner as the primary screening.
  • a sample of papillary thyroid cancer different from the primary screening (Group C: young people (under 30 years old) with cancer remaining in the thyroid gland.
  • Group A Old people (51 years old and over) with distant cancer
  • the expression level of these genes was quantified by TaqMan PCR using ABI ABI 7900HT and Microfludic card (Distinctive gene expression of human lung adenocarcinoma carrying LKBl mutations. Oncogene 23, 5084-5091, 2004).
  • the Micro Fluidic Card (Applied Biosystems, Foster City, Calif.) Containing Applied Biosystems fluorogenic 5 nuclease assays was used to detect gene expression differences among the 95 targets selected by the gene chip.
  • the relative level of gene expression was determined from fluorescence data generated during PCR real-time quantitative RT-PCR (TaqMan PCR) using the ABI PRISM 7900 HT Sequence Detection (Applied Biosystems).
  • An external endogenous control (FAM-GAPDH) was used as a standard in relative quantitation calculations. lOOng cDNA and TaqMan Universal Master Mix (Applied Biosystems) were used for the assembly.
  • these three genes are classified into group A (old people with poor prognosis !, group) and group C (young people) according to their gene expression levels. And a difference (over 9.0 times) between the A group (the elderly and the poor prognosis group) and the B group (the elderly and the good prognosis group). Significant differences were observed (more than 23.6 times). That is, these three genes are genes that showed a greater difference in prognosis (cancer malignancy) rather than age, and are considered to be very useful as markers for predicting the prognosis of papillary thyroid cancer.
  • RASGRF1, SFTPB, CYP4B1, C8orf4, EHF, CYP1B1 have large differences in expression levels between group A and group B (5.9 to 51.8 times), and papillary thyroid cancer It may be useful as a genetic marker for predicting the prognosis.
  • these 11 genes are considered to be useful in clinical examination as markers for predicting the prognosis of papillary thyroid cancer.
  • a combination of these genes or a combination with thyroglobulin is new and may be useful because it increases the diagnosis rate as a thyroid cancer tumor.
  • the expression level of these genes can be quantified at the blood level by using leukocytes in the blood as well as the surgical tissue, or the antigen-antibody method can be used at the protein level, which is convenient at the serum level. It can be measured, predicts the prognosis of patients, and can be useful for searching for recurrence and metastasis after surgery, which is very useful in outpatient practice.

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Abstract

La présente invention décrit un marqueur destiné à prédire le pronostic du carcinome papillaire de la thyroïde qui comprend au moins un gène sélectionné parmi le groupe composé de SUV39H2, CRLF1, TMPRSS2, FXYD3, MYCN, NMU, TREX1, KCNV1, CAPN6, PAPPA, SLC7A5(hLAT1), RASGRF1, SFTPB, CYP4B1, C8orf4, EHF et CYP1B1, un produit de transcription de ceux-ci ou un produit de traduction de ceux-ci.
PCT/JP2005/022436 2004-12-07 2005-12-07 Nouveaux marqueurs pour le pronostic predictif du carcinome papillaire de la thyroide WO2006062118A1 (fr)

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JP2008545400A (ja) * 2005-05-20 2008-12-18 ベリデックス・エルエルシー 甲状腺穿刺吸引分子分析
WO2010056374A2 (fr) * 2008-11-17 2010-05-20 Veracyte, Inc. Procédés et compositions de profilage moléculaire pour le diagnostic de maladies
US8669057B2 (en) 2009-05-07 2014-03-11 Veracyte, Inc. Methods and compositions for diagnosis of thyroid conditions
US9495515B1 (en) 2009-12-09 2016-11-15 Veracyte, Inc. Algorithms for disease diagnostics
US10114924B2 (en) 2008-11-17 2018-10-30 Veracyte, Inc. Methods for processing or analyzing sample of thyroid tissue
US10422009B2 (en) 2009-03-04 2019-09-24 Genomedx Biosciences Inc. Compositions and methods for classifying thyroid nodule disease
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