WO2014185466A1 - Procédé d'évaluation du pronostic du cancer du pancréas - Google Patents

Procédé d'évaluation du pronostic du cancer du pancréas Download PDF

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Publication number
WO2014185466A1
WO2014185466A1 PCT/JP2014/062875 JP2014062875W WO2014185466A1 WO 2014185466 A1 WO2014185466 A1 WO 2014185466A1 JP 2014062875 W JP2014062875 W JP 2014062875W WO 2014185466 A1 WO2014185466 A1 WO 2014185466A1
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ebi3
pancreatic cancer
prognosis
expression level
patient
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PCT/JP2014/062875
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English (en)
Japanese (ja)
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伸介 平岡
義典 石川
理恵 山崎
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独立行政法人国立がん研究センター
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Publication of WO2014185466A1 publication Critical patent/WO2014185466A1/fr

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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
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • 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
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to a prognostic evaluation method for pancreatic cancer that predicts the prognosis of pancreatic cancer.
  • Pancreatic cancer is one of the intractable cancers whose number of onsets and deaths hardly change. That is, pancreatic cancer is difficult to diagnose and treat and has the poorest prognosis among digestive malignant tumors. Therefore, in order to improve the prognosis of pancreatic cancer, it is important to establish an accurate treatment policy after evaluating the effectiveness of not only early diagnosis but also surgery and chemotherapy. Many markers for predicting the prognosis of cancer have been reported so far, but few markers for specifically predicting the prognosis of pancreatic cancer have been reported yet. The current situation is to wait for a determination from. Therefore, the development of biomarkers that enable appropriate selection of treatments for individual pancreatic cancer patients is urgently desired along with markers for early diagnosis.
  • EBI3 Epstein-Barr virus induced gene 3
  • EBI3 is a gene that was first expressed and attracted attention in a B cell line transformed in vitro with Epstein Barr virus (EBV) (Non-patent Document 1).
  • EBI3 is a component of IL-27 formed by heterodimerization with p28, a p35-related subunit of IL-12 (Non-patent Document 2).
  • EBI3 is a component of IL-35 formed by heterodimerization with IL-12 p35 (Non-patent Document 3).
  • IL-27 is thought to play an important role in initiating the Th1 immune response required for the immune response induced by IFN- ⁇ , while suppressing the differentiation of CD4 + T cells into Th2, Th17, iTreg, and IL Induces Tr1 differentiation of suppressor T cells producing -10 (Non-patent Document 4).
  • Non-Patent Document 5 the level of EBI3 increases in the blood of lung cancer patients, and the level of EBI3 gene expression in blood samples obtained from subjects (Patent Document 1) and the like have been reported that the subject can diagnose lung cancer and determine the risk of developing lung cancer.
  • the present invention identifies a marker useful for evaluating the prognosis of pancreatic cancer, evaluates the prognosis of pancreatic cancer using the marker, and evaluates the prognosis of pancreatic cancer using the marker It is related with providing the inspection kit for.
  • the present inventors used three cohorts of surgically resected cases of pancreatic cancer, and analyzed the transcription level, IL-12 family and IL-12 receptor family genes expressed in pancreatic cancer tissue.
  • the expression at the protein level was measured and analyzed (see FIG. 1)
  • the case group with high EBI3 gene expression showed a significantly longer survival time than the case group with low EBI3 gene expression, and EBI3 infiltrating the cancer tissue
  • the case group with a large number of expressed cells showed significantly longer survival than the case group with a small number of expressed cells, and found that the EBI3 gene and EBI3 can be significant markers for predicting the prognosis of pancreatic cancer.
  • the present invention relates to the following (1) to (6).
  • a method for evaluating the prognosis of pancreatic cancer comprising measuring the expression level of EBI3 in a biological sample isolated from a patient with pancreatic cancer.
  • the method according to (1) comprising the following steps a and b. a) measuring the expression level of EBI3 in a biological sample isolated from a patient with pancreatic cancer b) comparing the expression level of EBI3 with a control level (3) the expression level of EBI3 increases above the threshold level
  • the prognosis can be predicted by evaluating the pancreatic cancer tissue excised by surgery, for example, by the method of the present invention. It is also possible to monitor the status and progression of pancreatic cancer.
  • numerator (marker).
  • the graph on the left shows the relationship with survival rate (OS), and the graph on the right shows the relationship with recurrence-free survival (DFS).
  • the graph on the left shows the relationship with survival rate (OS), and the graph on the right shows the relationship with recurrence-free survival (DFS).
  • pancreatic cancer means a malignant tumor arising from the pancreas.
  • prognosis means a decrease or decrease in tumor volume due to surgical treatment or the like, or a course or ending after pancreatic cancer is reduced (eg, recurrence / tumor growth, life / death, etc.). To do. For example, life and death at a point in years or more after surgically complete tumor resection.
  • “good prognosis” means that the condition after attenuation or reduction of tumor growth due to surgical treatment or the like of a patient is not lethal for a long period of time (for example, 2-5 years). And cases of survival, non-metastasis, non-regression, non-recurrence, etc. That is, a state with a good prognosis includes a state in which even if some kind of disease such as recurrence / metastasis has been confirmed, its malignancy is low and it can survive.
  • a gene is used to include not only double-stranded DNA but also each single-stranded DNA such as sense strand and antisense strand constituting the DNA.
  • the length is not particularly limited. Therefore, in this specification, unless otherwise specified, a gene (DNA) is a double-stranded DNA containing human genomic DNA and a single-stranded DNA containing DNA (positive strand) and a sequence having a sequence complementary to the positive strand. Both double-stranded DNA (complementary strand) and fragments thereof are included.
  • the method for evaluating the prognosis of pancreatic cancer measures the expression level of EBI3 in a biological sample isolated from a patient with pancreatic cancer.
  • EBI3 expression of EBI3 gene and expression of EBI3 protein.
  • the EBI3 gene (Epstein-Barr virus induced gene 3) is a known gene registered as GenBank accession number: NM_005755.
  • the “EBI3 gene” includes not only the gene represented by the nucleotide sequence (SEQ ID NO: 1) but also a protein encoded by these (referred to as “EBI3” (SEQ ID NO: 2)) and biological activity. Genes encoding proteins for which are equivalent.
  • a DNA comprising a base sequence that hybridizes with a complementary sequence of the base sequence represented by SEQ ID NO: 1 under stringent conditions is included.
  • the stringent conditions are usually, for example, “1 ⁇ SSC, 0.1% SDS, 37 ° C.”, “0.5 ⁇ SSC, 0.1% SDS, 42 ° C. as washing conditions after hybridization. And “0.1 ⁇ SSC, 0.1% SDS, 65 ° C.”.
  • a complementary strand a strand consisting of a base sequence that is completely complementary to the target positive strand base sequence, and 90% or more, preferably 95% or more identity with the strand A chain consisting of a base sequence having can be exemplified.
  • the identity of the base sequence is calculated by, for example, the Lippmann-Pearson method (Lipman-Pearson method; Science, 227, 1435, (1985)), and genetic information processing software Genetyx-Win (Ver. 5.1.1). It can be calculated by analyzing the unit size to compare (ktup) as 2 using the software development) homology analysis (Search homology) program.
  • the biological sample used in the present invention may be a biological specimen isolated from a pancreatic cancer patient to be evaluated for prognosis, and is a patient's pancreatic cancer tissue.
  • the biological sample may be the sample separated and collected from the patient as it is, or may be pretreated appropriately for various measurements.
  • a paraffin section prepared from a specimen obtained from a patient can be used.
  • a protein extract or mRNA extract prepared from a specimen obtained from a patient can be used.
  • the method for measuring the expression level of EBI3 is not particularly limited as long as it can confirm EBI3 in a biological sample. That is, any method capable of detecting or quantifying the expression level of EBI3 may be used, and the expression level of EBI3 may be determined relative or absolutely. EBI3 expression may be detected or quantified at the protein level or may be detected or quantified at the nucleic acid (mRNA) level.
  • mRNA nucleic acid
  • an immunological measurement method using an antibody that specifically binds to EBI3 is simple and preferable.
  • the immunological measurement method include enzyme immunoassay (ELISA), radioimmunoassay, immunohistochemical staining, Western blot, immunoprecipitation, immunofluorescence, flow cytometry, and the like.
  • detection or quantification at the nucleic acid level include RT-PCR (preferably real-time RT-PCR), Northern blotting method, Branched DNA assay, in situ hybridization method and the like.
  • the antibody that specifically binds to EBI3 may be of any structure, size, and immunoglobulin class as long as it binds to EBI3, and may be monoclonal or polyclonal, labeled antibody, chimeric antibody It may be a humanized antibody. Moreover, it is also possible to use a part of an antibody (partial fragment) or a peptide containing a part of an antibody, and an antibody fragment that retains the binding action of an antibody to an antigen (EBI3). Examples of such antibody fragments include F (ab ') 2, Fab', Fab, single chain Fv (scFv) and the like.
  • Anti-EBI3 antibodies can be obtained by methods well known to those skilled in the art. For example, an expression vector for mammalian cells into which a polypeptide having all or part of EBI3 or a polynucleotide encoding the same is prepared and used as an antigen. After immunization of the animal with this antigen, immune cells obtained from the immunized animal and myeloma cells are fused to obtain a hybridoma, and an antibody is collected from the hybridoma culture. A monoclonal antibody against EBI3 can be obtained by subjecting the last collected antibody to antigen-specific purification using a polypeptide corresponding to EBI3 used as an antigen or a part thereof.
  • an animal is immunized with the same antigen as described above, blood is collected from the immunized animal, serum is separated from the blood, and antigen-specific purification using the antigen is performed on the serum. Can be obtained.
  • Antibody fragments can be obtained by enzymatic treatment of the obtained antibodies or using sequence information of the obtained antibodies.
  • the antibody can be labeled by a general method in this field, or can be labeled using a commercially available labeling kit.
  • the labeled antibody or a fragment thereof can be detected by using a device suitable for labeling as appropriate.
  • immunohistochemical staining method a known method can be adopted. For example, a biological sample separated from a patient is fixed in formalin by a conventional method, embedded in paraffin, sliced into tissue pieces, and pasted on a slide glass, and used as a slice sample. According to the characteristics of the antibody, the sectioned sample is appropriately activated by heat treatment with an autoclave or the like, and immunohistologically stained using Vector ABC method or DAKO EnVision detection system. Under the microscope, positive / negative can be determined by color development of EBI3.
  • nucleic acids are amplified by a known method using PCR or the like using appropriately designed primers. Examples of such methods include ARMS (Amplification Refractory Mutation System) method, RT-PCR (Reverse transcriptase-PCR) method and Nested PCR method.
  • the amplified nucleic acid is obtained by using a dot-blot hybridization method, surface plasmon resonance method (SPR method), PCR-RFLP method, In situ RT-PCR method, PCR using a nucleic acid complementary to the nucleic acid.
  • SSO sequence specific oligonucleotide
  • PCR-SSP sequence specific oligonucleotide
  • AMPFLP Amplifiable fragment length polymorphism
  • MVR-PCR MVR-PCR
  • PCRSSCP single strand conformation polymorphism
  • the expression level of EBI3 in the biological sample separated from the pancreatic cancer patient is measured, and the prognosis of the patient is evaluated based on the expression level of EBI3. Specifically, it is assessed by comparing the detected expression level of EBI3 with a control level.
  • the “control level” means, for example, a group of patients with a good prognosis (patient cancer patients whose prognosis was not poor, pancreatic cancer patients who are believed to have a poor prognosis), or pancreatic cancer.
  • the expression level of EBI3 in a group of healthy individuals who do not develop, or the expression level of EBI3 in a group of patients with a poor prognosis (a patient with a poor prognosis, a patient with a known prognosis).
  • the expression level of the target patient's EBI3 is close to, within the range of the expression level or higher than the expression level of the EBI3 in a group of healthy patients or a group of healthy subjects, Prognosis can be evaluated as good.
  • the expression level of EBI3 in a patient to be compared can be known, for example, by measuring the expression level of EBI3 in a sample derived from a patient whose prognosis is already known by the method of the present invention.
  • the prognosis evaluation in the present invention can also be performed by increasing / decreasing the expression level of EBI3.
  • the median value of the expression level of EBI3 gene or EBI3 is set to a threshold level (cutoff value), and the expression level of EBI3 in a patient-derived biological sample is compared with the threshold level.
  • the increase / decrease in the expression level of EBI3 in pancreatic cancer tissue can be used as an index by increasing / decreasing the number of EBI3-expressing cells infiltrating the pancreatic cancer tissue or expanding / reducing the expression region.
  • the threshold level is the sum of the number of EBI3-expressing cells in five fields of the objective lens ⁇ 20 (for example, three times) (Average) is 2 cells or more.
  • the test kit for evaluating the prognosis of pancreatic cancer of the present invention contains an antibody that specifically binds to EBI3, or an oligonucleotide that specifically binds to EBI3 mRNA or the EBI3 gene. That is, the test kit contains a test reagent for measuring the expression level of EBI3 in a biological sample separated from a patient. Specifically, including an antibody that specifically binds to EBI3 (anti-EBI3 antibody), ELISA, Western blot, immunochromatography, reagents for immunohistochemistry, or an oligonucleotide that specifically binds to EBI3 mRNA or EBI3 gene RT-PCR reagents and the like.
  • the nucleic acid specifically binding to the anti-EBI3 antibody, EBI3 gene or mRNA included in the kit can be obtained by a known method as described above.
  • the test kit can contain a labeling reagent, a buffer solution, a chromogenic substrate, a secondary antibody, a blocking agent, instruments and controls necessary for the test, and the like.
  • Example 1 Correlation between EBI3 gene expression and patient prognosis (1) Measurement of EBI3 gene expression level Extracting total RNA from surgically excised pancreatic cancer fresh tissue, and then using single-strand cDNA obtained by reverse transcription reaction as a template Then, using the following PCR primers, the gene was amplified using the quantitative RT-PCR method, and the expression level of the EBI3 gene was measured. Quantitative RT-PCR was performed with the Universal ProbeLibrary system of Roche Applied Science, and the expression level of ACTB gene was measured and compared as a control.
  • EBI3 5 'primer, gAAgTACTggATCCgTTACAAgC (SEQ ID NO: 3) 3 'primer, gAAggACgTggCTTCAATg (SEQ ID NO: 4) probe # 24 ACTB: 5 'primer, CCAACCgCgAgAAgATgA (SEQ ID NO: 5) 3 'primer, TCCATCACgATgCCAgTg (SEQ ID NO: 6) probe # 64 PCR conditions: 95 ° C for 10 seconds, [95 ° C for 15 seconds, 60 ° C for 1 minute] x 40 cycles
  • Tables 1 and 2 show the results of univariate and multivariate analysis using the Cox proportional hazard model.
  • EBI3 gene expression in pancreatic cancer tissue is considered to be an independent prognostic factor.
  • Example 2 Correlation between EBI3 protein expression and patient prognosis (1) Production of monoclonal antibodies against EBI3 Full-length human EBI3 is expressed in mammalian cells and Escherichia coli, purified EBI3 is immunized to mice, and hybridomas are prepared by conventional methods. Then, ELISA, Western blot, monoclonal antibody specific to EBI3 (clone E32-8, IgG1 K; clone E25-2, IgG1 K) using immunohistochemistry on formalin-fixed paraffin-embedded lymph node tissue as a screening method Established.
  • Tables 3 and 4 show the results of univariate and multivariate analysis using the Cox proportional hazard model.
  • the number of EBI3-expressing cells that infiltrate tumors in pancreatic cancer tissue is considered to be an independent prognostic factor.
  • the prognosis can be predicted and an appropriate treatment policy can be established.
  • an aggressive treatment strategy for example, intensive chemotherapy or radiation therapy
  • the need to select an aggressive treatment strategy for example, intensive chemotherapy or radiation therapy
  • the need to select an aggressive treatment strategy for example, intensive chemotherapy or radiation therapy
  • a more relaxed treatment strategy can be selected.
  • the method of the present invention can also be used to monitor the state or progression of pancreatic cancer. That is, EBI3 expression levels can be used to assess changes in the likelihood that a patient will die, recur, or metastasize. For example, by measuring the EBI3 expression level over time, changes in the prognosis of the patient can be known.

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Abstract

L'invention concerne, d'une part un procédé d'identification de marqueurs convenant à l'évaluation du pronostic du cancer du pancréas et à la prédiction du pronostic du cancer du pancréas au moyen desdits marqueurs, et d'autre part un kit de test conçu pour prédire le pronostic du cancer du pancréas au moyen desdits marqueurs. L'invention concerne également un procédé d'évaluation du pronostic du cancer du pancréas qui est caractérisé en ce qu'on mesure le niveau d'expression d'EBI3 dans un échantillon biologique prélevé chez un patient atteint du cancer du pancréas.
PCT/JP2014/062875 2013-05-14 2014-05-14 Procédé d'évaluation du pronostic du cancer du pancréas WO2014185466A1 (fr)

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Cited By (2)

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CN109402254A (zh) * 2018-09-04 2019-03-01 复旦大学附属华山医院 一种预测胰腺癌术后生存的LncRNA模型及检测试剂盒
CN114438217A (zh) * 2022-03-23 2022-05-06 深圳大学总医院 检测胰腺癌预后情况的试剂盒

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109402254A (zh) * 2018-09-04 2019-03-01 复旦大学附属华山医院 一种预测胰腺癌术后生存的LncRNA模型及检测试剂盒
CN109402254B (zh) * 2018-09-04 2024-03-08 复旦大学附属华山医院 一种预测胰腺癌术后生存的LncRNA模型及检测试剂盒
CN114438217A (zh) * 2022-03-23 2022-05-06 深圳大学总医院 检测胰腺癌预后情况的试剂盒

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