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WO2010064702A1 - Biomarqueur pour prédire un pronostic de cancer - Google Patents

Biomarqueur pour prédire un pronostic de cancer Download PDF

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Publication number
WO2010064702A1
WO2010064702A1 PCT/JP2009/070386 JP2009070386W WO2010064702A1 WO 2010064702 A1 WO2010064702 A1 WO 2010064702A1 JP 2009070386 W JP2009070386 W JP 2009070386W WO 2010064702 A1 WO2010064702 A1 WO 2010064702A1
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Prior art keywords
prognosis
cancer
gene
related gene
gene signature
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Japanese (ja)
Inventor
典子 後藤
悟 宮野
清哉 井元
麻衣 山内
類 山口
隆志 河野
淳 横田
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Japan Health Sciences Foundation
University of Tokyo NUC
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Japan Health Sciences Foundation
University of Tokyo NUC
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Publication of WO2010064702A1 publication Critical patent/WO2010064702A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • G01N33/57407—Specifically defined cancers
    • 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
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung
    • 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
    • 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

Definitions

  • Non-Patent Document 1 Lung cancer has been the most common and most fatal cancer in the world since 1985 (Non-Patent Document 1).
  • the overall 5-year survival rate is very low, and it has not improved even though its analysis efforts are being made.
  • Patients at an early stage of lung cancer are encouraged to undergo surgery, but the prognosis of patients after surgery appears to vary from recovery to death of metastatic recurrence.
  • Non-Patent Document 3 The report identified a link between previously undescribed tumor virulence and embryonic stem cell status.
  • Non-patent Document 4 Overexpression of epidermal growth factor receptor (EGFR) has been reported in many types of cancer including non-small cell lung cancer (NSCLC) (Non-patent Document 4). In recent studies, it has also been reported that the MAPK pathway including EGFR is most significantly mutated in lung adenocarcinoma (Non-patent Document 5).
  • NSCLC non-small cell lung cancer
  • a genetic test method for predicting recurrence risk is known as a diagnostic tool for prognosis of breast cancer (Patent Documents 1 and 2), and is sold as a genetic test “Mammaprint”.
  • An object of the present invention is to provide a gene signature useful for diagnosis of cancer, particularly lung cancer, and to provide a cancer diagnostic tool using such signature. Another object of the present invention is to identify novel prognostic markers for the early stage of lung cancer, particularly stage I.
  • the present inventors cultured normal primary lung epithelial cells (SAEC: primary small airway epithelial cells), and epithelial growth factor (EGF) or epidermal growth factor receptor ( The gene expression profiles of cells treated with EGFR) inhibitors or untreated cells were compared with each other, and the fluctuating gene group was narrowed down using a state space model.
  • SAEC primary small airway epithelial cells
  • EGF epithelial growth factor
  • the gene expression profiles of cells treated with EGFR) inhibitors or untreated cells were compared with each other, and the fluctuating gene group was narrowed down using a state space model.
  • the present inventors have succeeded in predicting the prognosis of lung cancer, in particular, early stage lung cancer, and completed the present invention.
  • a test method for predicting the prognosis of cancer comprising the step of measuring the expression level of a prognosis-related gene in a biological sample collected from a cancer patient for the transcription product or translation product of the gene, The method, wherein the gene is 2 to 277 genes selected from the following prognostic gene signature (1).
  • Prognostic gene signature (2) ADAM10; ADAM19 (includes EG: 8728); ADAM8; ADCY6; ADRBK2; ALOX15B; ARID3B; ATF2; BCAR3; BPGM; CASP4; CAT; CD3EAP; CDC42; CDKN1A; CENPF; CHODL; CHST2; CLEC2B; CSNK1D; CTGF; CXCL1; CXCR7; CYP2U1; DDEFL1; DDX21; DHCR7; DSCAM; DUSP1; DUSP4; EIF2AK2; ENC1; ETS2; EWSR1; FER1L4 (includes EG: 80307); FZD10; GAD1; GNB1; GRB10; HADH; HBEGF; HGS; HIST3H3; HMGCR; HMGCS1; HNRPM; HSD11B1; HSPA1A; HSPA5; HSPA
  • Prognostic gene signature (3) ADAM10; ADAM19 (includes EG: 8728); ADAM8; ADCY6; ADRBK2; ALOX15B; ATF2; BPGM; CASP4; CD3EAP; CDC42; CDC42EP2; CDKN1A; CENPF; CHST2; CLEC2B; COTL1; CNK1D; CXCR7; CYP1A1; CYR61; DDEFL1; DDX21; DUSP1; DUSP4; DUSP5; ETS2; FER1L4 (includes EG: 80307); FOSL1; FZD10; GAD1; GAPDH; GDNF; GNB1; GNG11; GNG4; HMGCR; HMGCS
  • a diagnostic agent for predicting the prognosis of cancer comprising a reagent for detecting the expression level of 2 to 277 prognosis-related genes selected from the following prognosis-related gene signature (1).
  • Prognostic gene signature (1) (same as above)
  • Prognostic gene signature (3) (same as above) [11] The diagnostic agent according to any one of [6] to [10], wherein the reagent is selected from a primer, a nucleic acid probe, and an antibody for a transcription product or translation product of a prognosis-related gene. [12] The following prognostic gene signature (1) immobilized on a solid surface: (same as above) An array for prognosis of cancer, comprising a nucleic acid probe that hybridizes to each of 2 to 277 genes selected from [13] The array according to [12], wherein the nucleic acid probe has a length of about 20 to 80 bases.
  • a method for predicting the possibility that a patient diagnosed with lung cancer will survive for a long time without recurrence of lung cancer (A) The expression level of a prognosis-related gene in cancer cells collected from the patient, the expression level of all transcripts or expression products in the cancer cells, or transcription for the transcription product or translation product of the prognosis-related gene Normalizing and determining the expression level of the product or reference set of expression products; (B) the step of subjecting the data obtained in step (a) to statistical analysis; and (c) the long-term survival probability of the patient is high or low based on the analysis result obtained in step (b).
  • Prognostic gene signature (1) (same as above) [15] A method for creating individual genome profiles for lung cancer patients, (A) a step of subjecting RNA extracted from cancer cells collected from the patient to gene invention analysis; (B) Prognostic gene signature (1): (same as above) Measuring the expression level in the cancer cell of 2 to 277 genes selected from the above, normalizing the expression level with respect to the control gene, and optionally comparing it with the amount found in the lung cancer reference tissue set; And (c) a method including a step of creating a report summarizing data obtained by the gene invention analysis.
  • test method and diagnostic agent of the present invention By using the test method and diagnostic agent of the present invention, it is possible to accurately predict the prognosis of cancer, and it is possible to select a treatment method that is more effective and has fewer side effects for cancer patients.
  • a more accurate prognosis can be predicted. It becomes possible.
  • the prediction method and genomic profile creation method of the present invention are expected to contribute to the progress of customized treatment for cancer patients.
  • the present invention contributes not only to the improvement of QOL of cancer patients and contribution to the medical economy, but also to the advancement of development of new therapeutic agents or treatment methods for cancer by selecting cancer patients corresponding to the treatment target in advance. Is expected to do.
  • FIG. 2 is a Kaplan-Meier curve showing that the prognosis of all stages of lung cancer patients can be predicted using the expression profile of all genes of the prognosis-related gene signature (2). It is a Kaplan-Meier curve which shows that the prognosis of a stage I lung cancer patient can be estimated using the expression profile of all the genes of a prognosis related gene signature (3).
  • FIG. 7 is a Kaplan-Meier curve showing that the prognosis-related gene signature (2) combined expression profile of all genes and patient clinical information can be used to predict the prognosis of all stages of lung cancer patients.
  • prognosis of cancer refers to a medical outlook on the course of cancer.
  • prognosis prediction refers to the possibility that a patient responds fragilely or unfavorably to a drug, the extent of such a reaction, removal of primary cancer by surgery and / or without recurrence for a certain period after chemotherapy. Mean any of the chances of survival.
  • the test method and prediction method of the present invention can be used clinically to determine a treatment method by selecting the most appropriate treatment method for a particular patient.
  • the test and prediction methods of the present invention may allow a patient to respond positively to a treatment plan such as surgical intervention, chemotherapy with a given drug or combination of drugs, or radiation therapy Or a useful tool for predicting whether a patient may survive for a long time after completion of surgery or chemotherapy, or other treatment.
  • a treatment plan such as surgical intervention, chemotherapy with a given drug or combination of drugs, or radiation therapy Or a useful tool for predicting whether a patient may survive for a long time after completion of surgery or chemotherapy, or other treatment.
  • the prognosis time for the prognosis of cancer may be before, during or after the treatment of cancer.
  • long-term survival means survival for 3 years or more after surgery or other treatment, preferably 5 years or more, more preferably 8 years or more, and most preferably 10 years or more.
  • the cancer in the present invention includes all cancers that occur in humans, but cancer caused by overexpressed EGFR family molecules or mutated cancer cells is desirable.
  • cancer caused by overexpression or mutation of EGFR family molecules include, but are not limited to, stomach cancer, lung cancer, breast cancer, ovarian cancer, and colon cancer.
  • the present invention can provide more useful information for lung cancer, which occupies the top cancer mortality and has a low 5-year survival rate.
  • Lung cancer is divided into small cell lung cancer and non-small cell lung cancer, and is classified into four stages, stage I, II, III and IV, respectively.
  • stage I means that cancer is localized in the lung and there is no metastasis to lymph nodes
  • stage II means that cancer is localized in the lung and metastasis only to lymph nodes in the lung.
  • stage III has not spread to other organs, but has advanced beyond stage II
  • stage IV has other organs Defined as metastasized.
  • stages I, II and III are classified into stages IA and IB, stages IIA and IIB, and stages IIIA and IIIB, respectively.
  • stage diagnosis of lung cancer see, for example, TNM classification: Lung Cancer Handling Rules, 5th edition, edited by the Japan Lung Cancer Society, Kanehara Publishing, 1999, pages 25-32.
  • the present invention is excellent in non-small cell lung cancer, particularly in stage I prognosis diagnosis and in all stage I-IV prognosis diagnosis.
  • the biological sample to be measured by the present invention is not particularly limited as long as it is derived from a cancer patient, but cancer tissue (including cancer cells), blood, lymph, lymph nodes (lymph where cancer has metastasized). Including clauses). Preferred are cancerous tissue (primary and metastatic) and lymph nodes suspected of having metastasized cancer.
  • polynucleotide means polyribonucleotides or polydeoxyribonucleotides, unmodified RNA or DNA or modified RNA or DNA .
  • a polynucleotide as defined herein includes single stranded and double stranded DNA, single stranded and double stranded DNA, single stranded and double stranded RNA, Such as RNA containing single-stranded and double-stranded regions, single-stranded or double-stranded, or hybrid molecules containing DNA and RNA containing single-stranded and double-stranded regions. It is not limited to.
  • polynucleotide in the present invention encompasses RNA or DNA, or a triplex region comprising both RNA and DNA.
  • the chains in such regions may be derived from the same molecule or different molecules.
  • the region may include all of one or more of the molecules, but more generally includes only one region of some molecules.
  • One of the molecules in the triplex region is often an oligonucleotide.
  • the term “polynucleotide” also specifically includes cDNA.
  • DNAs or RNAs having exceptional bases such as inosine or modified bases such as tritiated bases are also included within the scope of “polynucleotide”.
  • polynucleotide encompasses all chemically, enzymatically and / or metabolically modified forms of unmodified polynucleotides and is characterized by viruses and cells such as single and multicellular. Also encompassed are chemical forms of DNA and RNA.
  • differentially expressed gene means a gene whose expression is activated to a higher or lower level compared to that in a normal or control subject.
  • the term also encompasses genes whose expression is activated to higher or lower levels at different stages of the same disease.
  • differentially expressed genes may be activated or repressed at the nucleic acid level or protein level, or may undergo alternative splicing that results in different polypeptide products. Such differences can be evidenced, for example, by changes in polypeptide mRNA levels, surface expression, secretion or other partitioning.
  • Differential gene expression compares expression between two or more genes or their gene products, or compares expression ratios between two or more genes or their gene products, or Two products of the same gene that are processed differently, differing between normal subjects and specifically those suffering from the disease of cancer, or different at different stages of the same disease Comparing the products can be included.
  • Differential expression is, for example, temporal or intracellular expression of a gene or its expression product between normal and diseased cells, or between cells that have developed different diseases or are in different disease stages. Includes quantitative and qualitative differences in patterns.
  • expression of a gene is about 2-fold or more, preferably about 4-fold or more, more preferably about “Differential gene expression” is considered to be present when there is a difference of 6-fold or more, most preferably about 10-fold or more.
  • RNA transcripts are transcription determined by normalizing to the level of reference mRNA that may be all of the RNA determined in the specimen or a specific set of reference mRNAs. Used to mean product level.
  • gene amplification refers to the process of forming multiple copies of a gene or gene fragment in a specific cell or cell line.
  • the replication region (amplified strand of DNA) is often referred to as the “amplicon”.
  • the amount of mRNA produced that is, the level of gene expression, also increases in proportion to the copy number of the expressed gene.
  • the present invention provides a test method for predicting the prognosis of cancer.
  • the test method of the present invention includes a step of measuring the expression level of a prognosis-related gene in a biological sample collected from a cancer patient with respect to a transcription product or translation product of the gene.
  • the prognostic-related gene used as an index of the present invention is composed of 2 to 277 genes selected from the following prognostic-related gene signature (hereinafter sometimes simply referred to as “gene signature”) (1).
  • the prognosis-related gene is preferably composed of 3 or more, 5 or more, 10 or more, 15 or more, 20 or more, or 25 or more genes.
  • the individual genes constituting the gene signature (1) are known, and their base sequences and amino acid sequences are also known. A list of these 277 genes is shown in Tables 1-1 to 1-5.
  • the index should be 2 to 146 genes selected from the following prognostic gene signature (2) selected from the above gene signature (1) Is preferred.
  • the prognosis-related gene is more preferably composed of 3 or more, 5 or more, 10 or more, 15 or more, 20 or more, or 25 or more genes.
  • Prognostic gene signature (2) ADAM10; ADAM19 (includes EG: 8728); ADAM8; ADCY6; ADRBK2; ALOX15B; ARID3B; ATF2; BCAR3; BPGM; CASP4; CAT; CD3EAP; CDC42; CDKN1A; CENPF; CHODL; CHST2; CLEC2B; CSNK1D; CTGF; CXCL1; CXCR7; CYP2U1; DDEFL1; DDX21; DHCR7; DSCAM; DUSP1; DUSP4; EIF2AK2; ENC1; ETS2; EWSR1; FER1L4 (includes EG: 80307); FZD10; GAD1; GNB1; GRB10; HADH; HBEGF; HGS; HIST3H3; HMGCR; HMGCS1; HNRPM; HSD11B1; HSPA1A; HSPA5; HSPA
  • the test method of the present invention targets stage I lung cancer
  • the prognosis-related gene is more preferably composed of 3 or more, 5 or more, 10 or more, 15 or more, 20 or more, or 25 or more genes. Since specimens of stage I lung cancer are relatively homogeneous from the viewpoint of gene expression, it is said that it is generally difficult to predict the prognosis based on the difference in gene expression, but the gene signature (3) of the present invention is used. By using the index, prognosis can be easily predicted.
  • Prognostic gene signature (3) ADAM10; ADAM19 (includes EG: 8728); ADAM8; ADCY6; ADRBK2; ALOX15B; ATF2; BPGM; CASP4; CD3EAP; CDC42; CDC42EP2; CDKN1A; CENPF; CHST2; CLEC2B; COTL1; CNK1D; CXCR7; CYP1A1; CYR61; DDEFL1; DDX21; DUSP1; DUSP4; DUSP5; ETS2; FER1L4 (includes EG: 80307); FOSL1; FZD10; GAD1; GAPDH; GDNF; GNB1; GNG11; GNG4; HMGCR; HMGCS1; HNRPM; HOPX; HSPA1A; HSPA5; HSPA8; HSPB1; ID1; IER3; IGFBP2; IGFBP3; IGFBP6; IL1
  • the expression level of a prognosis-related gene can be measured by a method known per se using a diagnostic agent for predicting the prognosis of cancer of the present invention described below.
  • a method for measuring the expression level of the prognosis-related gene will be described later.
  • the diagnostic agent of the present invention contains a reagent for detecting the expression level of 2 to 277 prognostic genes selected from the gene signature (1).
  • the reagent may be any substance or means that can detect the expression level of a prognosis-related gene, and preferably comprises a primer, a nucleic acid probe, and an antibody for a transcription product or translation product of a prognosis-related gene. You can choose from a group.
  • the primer contained in the diagnostic agent of the present invention is not particularly limited as long as amplification and detection of a prognostic gene can be performed.
  • the primer size is at least about 12 bases in length, preferably about 15-100 bases in length, more preferably about 16-50 bases in length, and even more preferably about 18-35 bases in length.
  • the number of primers contained in the diagnostic agent of the present invention is not particularly limited, but the diagnostic agent of the present invention is classified into one type of prognosis-related gene.
  • two or more primers may be included. Two or more primers may be mixed in advance or may not be mixed. Such a primer can be prepared by a method known per se. The primer design method will be described later.
  • the nucleic acid probe contained in the diagnostic agent of the present invention is not particularly limited as long as it enables detection of a transcription product of a prognostic gene.
  • the nucleic acid probe can be DNA, RNA, modified nucleic acid, or a chimeric molecule thereof, but DNA is preferable in consideration of stability, convenience and the like. Nucleic acid probes can also be either single-stranded or double-stranded.
  • the size of the nucleic acid probe is not particularly limited as long as it can specifically hybridize to a transcript of a prognosis-related gene. For example, the length is about 15 or 16 bases or more, preferably about 15 to 1000 bases, more preferably about 20 to It is 500 bases long, more preferably about 20-80 bases long.
  • the nucleic acid probe may be provided in a form immobilized on a substrate like a nucleic acid array. Such a nucleic acid probe can be prepared by a method known per se.
  • the antibody contained in the diagnostic agent of the present invention is not particularly limited as long as it is an antibody that can specifically bind to a translation product of a prognosis-related gene.
  • the antibody against the translation product may be either a polyclonal antibody or a monoclonal antibody.
  • the antibody may also be a fragment of an antibody (eg, Fab, F (ab ′) 2 ), a recombinant antibody (eg, scFv).
  • the antibody may be provided in a form immobilized on a substrate such as a plate.
  • the antibody can be prepared by a method known per se.
  • a polyclonal antibody has a translation product of a prognostic gene or a partial peptide thereof (if necessary, a complex cross-linked to a carrier protein such as bovine serum albumin, KLH (Keyhole Limpet Hemocyanin)) as an antigen.
  • a commercially available adjuvant eg, complete or incomplete Freund's adjuvant
  • the antibody titer of a partially collected serum is determined by a known antigen-antibody reaction
  • the increase can be confirmed by collecting the whole blood about 3 to about 10 days after the final immunization and purifying the antiserum.
  • animals to which the antigen is administered include mammals such as rats, mice, rabbits, goats, guinea pigs, and hamsters.
  • Monoclonal antibodies can be obtained by cell fusion methods (eg, Takeshi Watanabe, principles of cell fusion methods and preparation of monoclonal antibodies, Akira Taniuchi, Toshitada Takahashi, “Monoclonal Antibodies and Cancer: Basic and Clinical”, 2-14). Page, Science Forum Publishing, 1985).
  • a translation product of a prognostic gene or the like is administered to a mouse subcutaneously or intraperitoneally 2-4 times together with a commercially available adjuvant, and the spleen or lymph node is collected about 3 days after the final administration, and white blood cells are collected.
  • the leukocytes and myeloma cells are fused to obtain a hybridoma that produces a monoclonal antibody against the translation product.
  • Cell fusion may be PEG method [J. Immunol. Methods, 81 (2): 223-228 (1985)] or voltage pulse method [Hybridoma, 7 (6): 627-633 (1988)].
  • a hybridoma producing a desired monoclonal antibody can be selected by detecting an antibody that specifically binds to an antigen from the culture supernatant using a well-known EIA or RIA method.
  • the culture of the hybridoma producing the monoclonal antibody can be performed in vitro or in vivo such as mouse or rat, preferably mouse ascites, and the antibody can be obtained from the culture supernatant of the hybridoma and the ascites of the animal, respectively.
  • the diagnostic agent of the present invention may be provided in the form of a kit including means for measuring a complex of a transcription product or translation product of a prognostic gene and a reagent in addition to the reagent.
  • the reagent and the measurement means included in the kit may be provided in a form isolated from each other, for example, stored in different containers.
  • the measuring means may be a detection substance labeled with a labeling substance according to the type of reagent.
  • the labeling substance examples include fluorescent substances such as FITC and FAM, luminescent substances such as luminol, luciferin, and lucigenin, radioisotopes such as 3 H, 14 C, 32 P, 35 S, and 123 I, biotin, streptavidin, and the like. And the like.
  • the diagnostic agent of the present invention may be provided in the form of a kit containing further components in addition to the reagent and the measurement means. More specifically, when the diagnostic agent of the present invention is provided in the form of a kit, it may contain additional components depending on the type of reagent and measuring means.
  • the kit may further comprise a reverse transcriptase, a nucleic acid extract or a nucleic acid extraction device.
  • the kit may further include a nucleic acid extract or a nucleic acid extraction device.
  • the measurement means is an antibody
  • the kit may further include a protein extract or a protein extractor.
  • the diagnostic agent of the present invention when provided in the form of a kit, it may further include means for collecting a biological sample from a cancer patient.
  • Such collection means is not particularly limited, and examples thereof include biopsy instruments such as biopsy needles and blood collection instruments.
  • the diagnostic agent of the present invention is preferably provided in the form of an array, and examples include nucleic acid arrays (synonymous with microarrays) and antibody arrays.
  • a preferred nucleic acid array is a cancer prognosis array comprising nucleic acid probes each of which is immobilized on a solid surface and hybridizes to 2 to 277 genes selected from prognosis-related gene signature (1).
  • the solid that becomes the support of the nucleic acid array is not particularly limited as long as it is a support that is usually used in the art, and examples thereof include membranes (for example, nylon film), glass, plastics, metals, and the like.
  • a form of the nucleic acid array in the present invention a form well known in the art can be used. For example, an array in which nucleic acids are directly synthesized on a support (so-called affiliometric method), or a nucleic acid is immobilized on the support. Array (so-called Stanford method), fiber type array, electrochemical array (ECA), etc. (for example, see JP-A-2005-102694).
  • the present invention provides a method for predicting the possibility that a patient diagnosed with lung cancer will survive for a long time without recurrence of lung cancer by applying the test method and diagnostic agent of the present invention.
  • the prediction method of the present invention includes the following steps: (A) The expression level of a prognosis-related gene in cancer cells collected from the patient, the expression level of all transcripts or expression products in the cancer cells, or transcription for the transcription product or translation product of the prognosis-related gene Normalizing and determining the expression level of the product or reference set of expression products; (B) the step of subjecting the data obtained in step (a) to statistical analysis; and (c) the long-term survival probability of the patient is high or low based on the analysis result obtained in step (b). A step of determining whether or not.
  • the prognostic genes used in the prediction method of the present invention are as described above.
  • the prediction method of the present invention allows not only long-term viability but also clinical stage classification (IA, IB, IIA, IIB, IIIA, IIIB, IV).
  • the present invention also provides a method for creating individual genomic profiles for lung cancer patients by applying the test methods and diagnostic agents of the present invention.
  • the method for creating a genome profile of the present invention comprises the following steps: (A) a step of subjecting RNA extracted from cancer cells collected from the patient to gene invention analysis; (B) The expression level in cancer cells of two or more genes selected from the prognosis-related gene signature (1) is measured, the expression levels are normalized with respect to the control gene, and if necessary, the tissue set for lung cancer reference And (c) generating a report summarizing the data obtained by the gene invention analysis.
  • prognostic genes used in the genome profiling of the present invention are as described above.
  • Gene expression profiling methods include methods based on polynucleotide analysis, methods based on polynucleotide sequencing, and methods based on proteomics.
  • the most commonly used method known in the art for quantifying mRNA expression in a sample includes Northern blotting and in situ hybridization ((Parker & Barnes, Methods in Molecular Biology 106: 247).
  • RT-PCR Gene expression profiling by PCR
  • RT-PCR is the most sensitive and most flexible quantification method, comparing mRNA levels in different sample populations, normal and cancerous tissues, with or without drug treatment, It can be used to characterize expression patterns, to distinguish closely related mRNAs, and to analyze RNA structures.
  • the first step is to isolate RNA from the biological sample.
  • the starting material is generally total RNA isolated from human cancers or cancer cell lines and corresponding normal tissues or cell lines, respectively.
  • RNA can be expressed in a variety of primary cancers, metastatic cancers or cancer cell lines, including breast, lung, colon, prostate, brain, liver, kidney, pancreas, spleen, thymus, testis, ovary, uterus, and other cancers. Or from a biological sample taken from a healthy donor. If RNA is derived from primary cancer or metastatic cancer, RNA can be extracted from frozen or stored paraffin-embedded and fixed (formalin-fixed) tissue samples.
  • RNA isolation can be performed according to the manufacturer's instructions using a purification kit, buffer set, and protease obtained from a manufacturer such as Qiagen.
  • a purification kit for example, total RNA of cultured cells can be isolated using Qiagen's RNeasy mini column.
  • Other commercially available RNA isolation kits include the registered trademark MasterPure total DNA and RNA purification kit (registered trademark EPICENTRE, Madison, WI), and a paraffin block RNA isolation kit (Ambion, Inc.). is there.
  • Total RNA from tissue samples can be isolated using RNA Stat-60 (Tel-Test).
  • RNA prepared from cancer may be purified by, for example, cesium chloride concentration gradient centrifugation.
  • RNA cannot be used as a template for PCR
  • the first step in gene expression profiling by RT-PCR is to reverse-transcribe the RNA template into cDNA and then amplify it exponentially in a PCR reaction.
  • the two most widely used reverse transcriptases are avian myeloblastosis virus reverse transcriptase (AMV-RT) and Moloney murine leukemia virus reverse transcriptase (MMLV-RT).
  • AMV-RT avian myeloblastosis virus reverse transcriptase
  • MMLV-RT Moloney murine leukemia virus reverse transcriptase
  • the reverse transcription process is generally initiated with specific primers, random hexamers, or oligo-dT primers, depending on the environment and the purpose of expression profiling.
  • the extracted RNA can be reverse transcribed using the GeneAmp RNA PCR kit (Perkin Elmer, CA, USA) according to the manufacturer's instructions.
  • the obtained cDNA can be used as a template in the
  • thermostable DNA-dependent DNA polymerases are used in the PCR process, but generally have 5′-3 ′ nuclease activity but no 3′-5 ′ proofreading exonuclease activity.
  • Taq DNA polymerase is used. That is, the registered trademark TaqMan® PCR generally uses the 5 ′ nuclease activity of Taq polymerase or Tth polymerase to hydrolyze the hybridization probe bound to its target amplicon, but the same 5 'An enzyme having nuclease activity can also be used.
  • Two oligonucleotide primers are used to generate an amplicon unique to the PCR reaction.
  • a probe In order to detect the base sequence existing between the two primers, another oligonucleotide, ie, a probe is designed.
  • This probe cannot be extended by Taq DNA polymerase enzyme, and is labeled with a fluorescent dye for reporter and a fluorescent dye for quencher.
  • a fluorescent dye for reporter When these two types of dyes are on the probe and close to each other, the light generated by the laser from the reporter dye is quenched by the quencher dye.
  • the Taq DNA polymerase enzyme cleaves the probe in a template-dependent manner. The resulting probe fragment dissociates into solution, releasing the signal from the released reporter dye from the quenching action of the second fluorophore. Since one molecule of the reporter dye is released each time a new molecule is synthesized, the data can be interpreted quantitatively based on the detection of the reporter dye that is not quenched.
  • the registered trademark TaqMan® RT-PCR is, for example, the registered trademark ABI® PRISM® 7700 Sequence Detection Kit (Perkin-Elmer-Applied® Biosystems, ® Foster® City, CA, USA) or Lightcycler (Roche® Molecular Chemistry's commercially available device). Can be used.
  • the 5 'nuclease method is performed on a real-time quantitative PCR device such as the registered trademark ABI® PRISM® 7700 sequence detection kit.
  • This device consists of a thermocycler, laser, charge coupled device (CCD) camera and computer. This apparatus amplifies samples that are in a 96-well format on a thermocycler. During the amplification process, the fluorescence signal generated by the laser is collected in real time through a fiber optic cable for all 96 wells and detected by CCD.
  • the device includes software for operating the instrument and for analyzing the data.
  • the 5 'nuclease assay data is first expressed as Ct or threshold cycle.
  • Ct critical cycle
  • ⁇ RT-PCR is usually performed using an internal standard to minimize error and sample-to-sample variation effects.
  • An ideal internal standard is one that is expressed at a constant level in various tissues and is not affected by experimental processing.
  • the most frequently used RNAs to normalize gene expression patterns are the housekeeping genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and ⁇ -actin mRNA.
  • a newer variation of the RT-PCR technique is real-time quantitative PCR, which determines PCR product accumulation with a dual-labeled fluorogenic probe (eg, registered trademark Taqman probe).
  • Real-time PCR is quantitative using the normalization gene contained in the sample or the housekeeping gene for RT-PCR in quantitative competitive PCR used to normalize internal competitor molecules for each target sequence. Also suitable for comparative PCR. For further details see, for example, Held et al. Genome Research 6: 986-994 (1996).
  • the PCR product of the competitor molecule and cDNA is subjected to primer extension treatment to generate different mass signals for the PCR product derived from the competitor molecule and cDNA.
  • primer extension treatment to generate different mass signals for the PCR product derived from the competitor molecule and cDNA.
  • these products are purified, they are dispensed into a chip array that is preloaded with components necessary for analysis by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF MS).
  • MALDI-TOF MS matrix-assisted laser desorption / ionization time-of-flight mass spectrometry
  • the cDNA present in the reaction solution is quantified by analyzing the ratio of the peak region of the created mass spectrum. For further details see, for example, Ding and Cantor, Proc. Natl. Acad. Sci. USA 100: 3059-3064 (2003).
  • Additional PCR techniques include, for example, the differential display method (Liang and Pardee, Science 257: 967-971 (1992)); amplified fragment length polymorphism (iAFLP) (Kawamoto et al., Genome Res. 12: 1305- 1312 (1999)); registered bead array technology (Illumina, San Diego, CA; Olifant et al., Discovery of Markers for Disease (Supplement to Biotechniques, 18 et al., Et al., Et al. )); Lum available in the market for rapid gene expression assays a bead array for gene expression (BADGE) (Yang et al., Genome Res.
  • iAFLP amplified fragment length polymorphism
  • BADGE bead array for gene expression
  • RNA Differential gene expression can also be identified or confirmed using microarray technology. That is, the expression profile of prognostic genes can be determined using microarray technology in either fresh cancer tissue or paraffin-embedded cancer tissue.
  • the polynucleotide sequence of interest (such as cDNA and oligonucleotide) is plated or aligned on a microchip substrate. The aligned sequence is then hybridized with a specific DNA probe derived from the target cell or tissue.
  • the source of RNA is cancer or a cancer cell line and total RNA isolated from the corresponding normal tissue or cell line.
  • RNA is derived from primary cancer, RNA can be extracted from frozen or stored paraffin-embedded and fixed (formalin-fixed) tissue samples. It can be prepared and stored very commonly.
  • PCR amplified insert sequences of cDNA clones are loaded onto a substrate at high density.
  • a fluorescently labeled cDNA can be prepared by incorporating a fluorescent label by reverse transcription of RNA extracted from the target tissue. Labeled cDNA applied to the chip hybridizes with specificity to DNA spots on the array. After high stringency washing to remove non-specific binding, the chip is scanned by another detection method such as a confocal laser microscope or a CCD camera. Quantifying the hybridization of the components on each array makes it possible to estimate the abundance of the corresponding mRNA. Two-color fluorescence methods are used to hybridize pairs of pairs of cDNAs made from two RNA sources and labeled separately.
  • the relative abundance of transcripts corresponding to each specific gene from these two sources is determined simultaneously.
  • simple and rapid evaluation of the expression patterns of many genes becomes available.
  • Such methods have been shown to have the sensitivity required to detect rare transcripts that are expressed only a few copies per cell, and reproducibly detect differences in expression levels of at least about twice. (Schena et al., Proc. Natl. Acad. Sci. USA 93 (2): 106-149 (1996).
  • it can also be detected by a one-color fluorescence method.
  • Microarray analysis methods can be performed by commercially available equipment, such as using Affymetrix GeneChip technology, Agilent Technologies microarray technology or Incyte microarray technology, according to the manufacturer's instructions.
  • the gene expression continuous analysis method is a method capable of simultaneously and quantitatively analyzing a large number of gene transcripts without the need to prepare a hybridization probe for each transcript. First, if a short sequence tag (approximately 10-14 base pairs) is obtained from a unique position within each transcript, a tag is generated that contains sufficient information to identify each transcript individually. Multiple transcripts can then be ligated together to form long, continuous molecules that can be sequenced and reveal the identity of multiple tags simultaneously. The expression pattern of a population of transcripts can be assessed quantitatively by determining the amount of each tag and identifying the gene corresponding to each tag. For further details see, for example, Velculescu et al. , Science 270: 484-487 (1995); and Velculescu et al. , Cell 88: 243-51 (1997).
  • Immunohistochemistry is also suitable for detecting the expression level of the prognostic genes of the present invention. That is, expression is detected using an antibody specific for each prognostic gene product. These antibodies can be detected by directly labeling the antibodies themselves with, for example, radioactive labels, fluorescent labels, biotin, or hapten labels such as horseradish peroxidase or alkaline phosphatase. Alternatively, an unlabeled primary antibody is used with a labeled secondary antibody, including antisera, polyclonal antisera, or monoclonal antibodies specific for the primary antibody. Immunohistochemistry protocols and kits are well known in the art and are commercially available.
  • proteomics is defined as all of the proteins present in a sample (eg, tissue, organism, or cell culture) at a given time.
  • proteomics involves examining the overall change in protein expression in a sample (also referred to as “expression proteomics”).
  • Proteomics generally includes the following steps: (1) separation of each protein in a sample by 2-D gel electrophoresis (2-D PAGE), (2) identification of each protein recovered from this gel, For example, mass spectrometry or N-terminal sequencing and (3) data analysis using bioinformatics.
  • the proteomic method is a useful adjunct to other gene expression profiling methods and can be used alone or in combination with other methods to detect the products of the prognostic genes of the present invention.
  • the gene expression data is analyzed to determine the best treatment options available to the patient, based on the characteristic gene expression patterns identified in the examined cancer samples, depending on the predicted likelihood of cancer prognosis. Identify.
  • An important aspect of the present invention is to provide prognostic information using measured expression of certain genes by lung cancer tissue.
  • this assay generally measures and incorporates the expression of certain normalized genes, such as well-known housekeeping genes such as GAPDH and Cyp1.
  • normalization can be based on the mean or median (Ct) of signals of all measured genes, or a large subset thereof. The measured and normalized amount of patient cancer mRNA is compared for each gene with the amount found in the lung cancer tissue reference set.
  • N the number of lung cancer tissues (N) in this reference set is large enough, it is certain that another reference set (as a whole) will behave essentially the same. If this condition is met, the identity of each lung cancer tissue in a specific set should not have a significant effect on the relative amount of genes measured.
  • PCR primers and probes are designed based on intron sequences present in the gene to be amplified.
  • the first step in primer / probe design is to reveal intron sequences within the gene. This is described in Kent, W. et al. J. et al. Genome Res. 12 (4): 656-64 (2000), and can be performed by published software such as DNA BLAST, or by BLAST software including variations thereof.
  • PCR primer design The most important factors considered in PCR primer design are primer length, melting temperature (Tm), and G / C content, specificity, complementary primer sequence, and 3'-end sequence, etc. .
  • optimal PCR primers are usually 17-30 bases in length and contain about 20-80% G + C bases, eg, about 50-60%.
  • Tm is between 50 and 80 ° C, for example about 50 to 70 ° C is generally preferred.
  • EGF epidermal growth factor
  • SAECs Cell Culture Normal human peripheral airway epithelial cells
  • SAGM medium CAMBREX
  • A549, PC9 and PC13 in RPMI 1640 medium supplemented with (Nakarai tesque) 10% fetal calf serum (FBS) (JRH Biosciences), 100 U / ml penicillin (Nakarai tesque) and 100 ⁇ g / ml streptomycin (Nakarai tesque) Grow.
  • the cells were cultured under conditions of 37 ° C. and 5% CO 2 .
  • Antibody Anti-human EGFR antibody was purchased from Medical & Biological Laboratories co.
  • Anti-c-ErbB2 / c-Neu (Ab-3) antibody was purchased from Calbiochem.
  • Anti-erbB-3 / HER-3 (clone2F12) antibody was purchased from upstate.
  • MAPK mitogen activated protein kinase
  • HRP horseradish peroxidase conjugated anti-mouse / rat / rabbit immunoglobulin G (IgG) antibody
  • IgG immunoglobulin G
  • HRP conjugated anti-goat IgG Ab Santa Cruz Biotechnology
  • Cell Proliferation Assay Cells are seeded on 96-well collagen-coated plates with medium containing the substance to be tested (EGF (100 ng / ml) or EGFR inhibitor (0.5 ⁇ M)) and the cells are incubated at 37 ° C. for 24 hours or Incubated for 72 hours. RNA was recovered after cell number was determined using CellTiter 96 (registered trademark, Promega) according to the manufacturer's instructions.
  • EGF 100 ng / ml
  • EGFR inhibitor 0.5 ⁇ M
  • RNA isolation Total RNA was isolated from each sample using TRIzol® reagent (Invitrogen) according to the manufacturer's instructions. The quality and integrity of total RNA was evaluated with 2100 Bioanalyzer (Agilent Technologies). RNA samples with a complete RNA number (RIN) greater than 8 were used for further analysis.
  • RNA samples were labeled using an Agilent low RNA input linear amplification kit (Agilent Technologies) according to the manufacturer's instructions. Briefly, 500 ng of total RNA was amplified and labeled using Cyanine 3-CTP. Hybridization was performed using gene expression hybridization kit (Agilent Technologies) according to the manufacturer's instructions. That is, 1.65 ⁇ g of sample cRNA was subjected to fragmentation (30 minutes, 60 ° C.), then in a rotary oven (10 rpm, 65 ° C., 17 hours), 44K Agilent Whole Human Genome Oligo Microarray (G41112F) (Agilent Technologies) Hybridization was performed above. Slides were disassembled and washed with Agilent Gene Expression Wash Buffers 1 and 2 (Agilent Technologies) according to the manufacturer's instructions.
  • Agilent Gene Expression Wash Buffers 1 and 2 Agilent Gene Expression Wash Buffers 1 and 2 (Agilent Technologies) according to the manufacturer's instructions.
  • Microarray data acquisition and processing Microarrays were scanned with a dynamic autofocus microarray scanner (Agilent Technologies) using parameters provided by Agilent (Green PMT set to 100%, scan resolution set to 5 ⁇ m).
  • Feature Extraction Software v7 (Agilent Technologies) was used to obtain raw signal values and qualitative flags (present, bound, absent).
  • Median shift normalization was applied to the signal from each microarray. That is, the median of the processed signal on the microarray is 1. Normalized signals after log transformation with base were used.
  • FIGS. 1 and 2 show the relationship between prognosis-related gene signatures (1), (2) and (3) obtained using microarray data and state space model analysis processed as described above.
  • the prognosis-related gene signature (2) corresponds to SetD_sub2 in FIG. 1
  • the prognosis-related gene signatures (1) and (3) correspond to Set Ip04 and Set Ip04s01 in FIG. 2, respectively.
  • 3-5 are Kaplan-Meier curves that predicted prognosis of lung cancer using prognosis-related gene signatures (2) and (3). From this result, it was found that signature (2) is effective for all stages of lung cancer and signature (3) is effective for stage I lung cancer.
  • the cancer prognosis diagnosis method advances, and it becomes possible to select a treatment method that is more effective and has fewer side effects for cancer patients.
  • the present invention is expected to contribute to the improvement of QOL of cancer patients and the medical economy.

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Abstract

L'invention concerne une signature génétique qui est utile pour le diagnostic d'un cancer, en particulier, d'un cancer du poumon ; un procédé pour diagnostiquer un cancer utilisant la signature ; un procédé d’analyse pour prédire le pronostic de cancer, qui comporte une étape de détermination du niveau d'expression d'un gène se rapportant au pronostic, c’est-à-dire le niveau d'expression d'un produit de transcription du gène ou d'un produit de traduction du gène, dans un échantillon biologique prélevé sur un patient atteint d'un cancer, le gène étant choisi parmi 277 gènes compris dans une signature génétique se rapportant au pronostic (1) (la signature génétique se rapportant au pronostic est telle que définie dans la description), et un agent de diagnostic pour prédire le pronostic de cancer, qui comporte un réactif pour détecter le niveau d'expression du gène se rapportant au pronostic.
PCT/JP2009/070386 2008-12-05 2009-12-04 Biomarqueur pour prédire un pronostic de cancer Ceased WO2010064702A1 (fr)

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