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WO2012060636A2 - Procédé pour le diagnostic du cancer de l'estomac - Google Patents

Procédé pour le diagnostic du cancer de l'estomac Download PDF

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Publication number
WO2012060636A2
WO2012060636A2 PCT/KR2011/008314 KR2011008314W WO2012060636A2 WO 2012060636 A2 WO2012060636 A2 WO 2012060636A2 KR 2011008314 W KR2011008314 W KR 2011008314W WO 2012060636 A2 WO2012060636 A2 WO 2012060636A2
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Prior art keywords
met
additive
protein
gastric cancer
level
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English (en)
Korean (ko)
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WO2012060636A3 (fr
Inventor
박수경
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SNU R&DB Foundation
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SNU R&DB Foundation
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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
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
    • 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
    • G01N33/57446—Specifically defined cancers of stomach or intestine
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • 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
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • Helicobacter pylori is a bacterium found in about 50% of the world's humans. It can cause gastric ulcers and severe gastric cancer, and recent studies have shown that among those infected with Helicobacter bacterium, they are infected with the cytotoxic protein (CagA). It was found that the risk of gastric cancer was 3.7 times higher than in the other cases.
  • c-Met protein a hepatocyte growth factor (HGF) receptor
  • c-Met protein is a transmembrane protein that is transcribed from the proto-oncogene.
  • Mature c-Met proteins are heterodimer ⁇ (50-kDa) and ⁇ (145-KDa) chains linked by disulfide bonds (Giordano S et al. , 1988).
  • the ⁇ -chain links the HGF binding domain outside the cell membrane with the tyrosine-kinase active domain inside the cell (Bottaro DP et al. , 1991, Dean M et al. , 1985).
  • the entire c-Met protein Upon proteolysis, the entire c-Met protein is separated from the endothelial cell membrane to form a soluble truncated c-Met protein.
  • the soluble truncated c-Met protein consists of the whole cell outer part of the membrane domain and binds HGF competitively with the whole c-Met protein (Wajih N et al., 2002). The selective binding of these soluble truncated c-Met proteins suggests the possibility of forming opposite cell signaling to inhibit cancer development.
  • the present invention to solve the above problem, measuring the level of soluble truncated c-Met protein in a biological sample; And comparing the protein level with that of a normal individual.
  • the present invention provides a composition for diagnosing gastric cancer comprising an agent for measuring the level of soluble truncated c-Met protein.
  • soluble truncated c-Met protein which can be easily collected from blood, is used as a marker, and thus gastric cancer can be diagnosed easily and efficiently.
  • the present invention comprises the steps of measuring the level of soluble truncated c-Met protein in a biological sample; And comparing the protein level with that of a normal individual.
  • the inventors of the present invention continue to use the soluble truncated c-Met protein as a marker for diagnosing a disease, and in patients with gastric cancer, soluble truncated in the blood when gastric cancer is neared.
  • the present inventors have found that the c-Met protein concentration is reduced, thus completing the present invention.
  • the biological sample is not limited now, but may specifically use tissue, cells, blood or plasma, preferably blood or plasma.
  • the present invention is useful in that a protein that is easily detected in blood is used as a marker.
  • Blood may be taken, for example, from veins, arteries or capillaries by methods known in the art, and more specifically, blood may be obtained by taking venous blood from the subject's arm via a syringe, but not limited thereto. It doesn't happen.
  • the measurement of the level of the soluble truncated c-Met protein is performed by a method of contacting a sample with an antibody that specifically recognizes the protein and measuring its antigen-antibody complex formation.
  • the amount of the antigen-antibody complex formed can be quantitatively measured through the size of a signal of a detection label, and the detection label is not particularly limited thereto, but enzymes, fluorescent materials, ligands, luminescent materials, and microparticles can be measured. At least one selected from the group consisting of redox molecules and radioisotopes may be used.
  • Methods for measuring protein levels include Western blot, ELISA, radioimmunoassay, radioimmunoassay, oukteroni immunodiffusion, rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, pricipitin Competitive or non-competitive known analytical methods such as reactions, gel diffusion prispicin response, aggregation assays, fluorescence immunoassays, Protein A immunoassays, FACS, protein chips, and the like can be used, but are not limited thereto. Can be performed.
  • the ELISA is a direct sandwich ELISA using another labeled antibody that recognizes an antigen in a complex of an antibody attached to a solid support, and reacted with another antibody that recognizes an antigen in a complex of an antibody attached to a solid support and an antigen. And various ELISA methods such as indirect sandwich ELISA using a labeled secondary antibody which then recognizes this antibody.
  • the diagnostic method comprises 10 to 50 consecutive DNA sequences comprising a 27th base (polymorphic site) in one or more sequences selected from the group consisting of SEQ ID NOs: 1 to 3 or Identifying the presence of a complementary sequence.
  • the inventors of the present invention further examined the gene polymorphism present in the gene of c-Met protein, and found that the SNP represented by SEQ ID NO: 1 to SEQ ID NO: 3 is significant with gastric cancer, and it is soluble in truncated c- Analysis with information on the level of Met protein found that the accuracy of gastric cancer diagnosis was higher.
  • nucleotide sequences of the SNPs of SEQ ID NOs: 1 to 3 are shown in Table 1 below.
  • Table 1 SEQ ID NO: rs number (ncbi gene bank) Base sequence from 5'- One rs41739 TATGTTAAGCAAAACATACTTTAGAA [A / G] CAAATGAAAAAGGCAATTGAAAATC 2 rs6566 TTGTTCTGATAAATCATGCAATTAAA [A / G] TAAAGTGATGCAACATCTTGTATAC 3 rs41738 GCTACTCTGATCTAATGAATGTGAAC [A / G] TGTAGATGTTTTGTGTGTATTTTTTTTTTTTTT
  • the position of the SNP in each of the polynucleotides is the 27th base, and the allelic types that may appear are shown in parentheses.
  • the presence of the sequence may be obtained by obtaining a nucleic acid sample from a sample; And detecting the presence of the sequence in the sample.
  • the sequence is 10 to 50 consecutive DNA sequences including the 27th base (polymorphic region) in one or more sequences selected from the group consisting of SEQ ID NOs: 1 to 3 or complement thereof
  • the 27th base is G for SEQ ID NO: 1; A for SEQ ID NO: 2; In case of SEQ ID NO: 3, it may be G.
  • the nucleic acid can be isolated from all cells, such as blood, skin cells, mucosal cells and hair of the diagnostic object.
  • the nucleic acid may be DNA or RNA, preferably DNA.
  • the method of extracting nucleic acid from the cell is not particularly limited, and techniques known in the art or commercially available kits for extracting nucleic acids can be used. For example, phenol / chloroform extraction and protease K treatment can be used.
  • Kits for DNA or RNA extraction are available from Qiagen, Inc, and Stratagene.
  • cDNA may be prepared and used through reverse transcription.
  • sequence analysis may be performed. Sequencing may use any method known in the art, and the present invention is not limited thereto, but may include, but is not limited to, an autobase sequencer, pyrosequencing, PCR-RELP (restriction fragment length polymorphism), PCRSSCP (single strand conformation polymorphism), PCR-SSO (specific sequence oligonucleotide), PCR-SSO and dot hybridization combined ASO (allele specific oligonucleotide) hybridization, TaqMan-PCR, MALDI-TOF / MS, Any one or more selected from known methods such as RCA method (rolling circle amplification), HRM (high resolution melting) method, primer extension method, Southern blot hybridization method and dot hybridization method can be used.
  • the diagnostic method may further comprise the step of confirming the value of the genetic risk score of CRK, CRKL, CSK, GRB2, MET, PTPN11 and SRC.
  • the inventors of the present invention further examined gene polymorphisms present in seven protein genes that bind CagA, such as c-Met protein, and present in seven genes of CRK, CRKL, CSK, GRB2, MET, PTPN11 and SRC.
  • Each beta ( ⁇ ) value was obtained through statistical analysis on 112 SNPs.
  • the genetic risk score value was calculated by conventional methods known in the art, and it was found that analyzing the information with the level of soluble truncated c-Met protein increases the accuracy of gastric cancer diagnosis. .
  • the step of comparing the protein level with the protein level of the normal individual can be used to compare the protein level in the biological sample of the suspected gastric cancer patient, absolute and relative using a sample of a normal person as a control.
  • the sample can be diagnosed as gastric cancer.
  • Absolute comparisons indicate that if the concentration of the soluble truncated c-Met protein in the sample is less than 14-15 ng / ml, 14.5-15 ng / ml, 14.6-14.8 ng / ml, or 14.7 ng / ml It can be diagnosed with
  • genetic risk score values can be obtained by averaging the values of each gene, and are coded as 2 for risk-transformation, 1 for heterozygosity, and 0 for non-risk-transformation.
  • the genetic risk score is 25 or more, preferably 26 or more can be diagnosed as gastric cancer.
  • the present invention provides a composition for diagnosing gastric cancer comprising an agent for measuring the level of soluble truncated c-Met protein.
  • the agent measuring the protein level may be an antibody specific for the soluble truncated c-Met protein.
  • the antibody includes all polyclonal antibodies, monoclonal antibodies and recombinant antibodies that specifically bind to soluble truncated c-Met proteins.
  • Antibodies of the invention also comprise functional fragments of the complete form and antibody molecules having two full length light chains and two full length heavy chains such as Fab, F (ab '), F (ab') 2 and It also includes the form of Fv.
  • Antibodies that specifically bind to the soluble truncated c-Met protein include both conventional antibodies as well as antibodies that can be prepared by known methods. Specifically, the soluble truncated c-Met protein is injected into the animal, and the soluble truncated c-Met protein is well known in the art, which is a method well known in the art to obtain a serum containing an antibody by collecting blood from the animal. Specific polyclonal antibodies can be prepared. In addition, soluble truncated c-Met protein specific monoclonal antibodies can be prepared using hybridoma methods or phage antibody library techniques.
  • the gastric cancer diagnostic composition is 10 to 50 consecutive DNA sequences including the 27th base (polymorphic region) in one or more sequences selected from the group consisting of SEQ ID NOs: 1 to 3 or It may further comprise a probe for the detection of a polynucleotide consisting of a complementary sequence or a complementary polynucleotide thereof.
  • the probe refers to a natural or modified nucleic acid fragment such as RNA or DNA that can be hybridized to mRNA and a specific nucleotide sequence and labeled to confirm the presence or absence of a specific nucleotide.
  • Probes used for hybridization may be prepared in the form of oligonucleotide probes, single stranded DNA probes, double stranded DNA probes, RNA probes, and the like.
  • Conditions suitable for hybridization can be determined by adjusting the temperature, ionic strength (buffer concentration), the presence of compounds such as organic solvents, and the like. Such stringent conditions can be determined differently depending on the sequence being hybridized.
  • primer pairs that specifically amplify a specific region of the gene or probes that specifically recognize a specific region of the gene from known marker gene nucleic acid sequences of the present invention and are known in the art. It can be synthesized chemically. In addition, modifications can be made using labels such as radioisotopes, fluorescent molecules, biotin, and the like to provide detectable signals directly or indirectly.
  • composition for diagnosing gastric cancer of the present invention may be prepared as various types of gastric cancer diagnostic kits further including components, detection reagents, or devices suitable for each type of kit.
  • kits for diagnosing gastric cancer further includes a test tube or other suitable container, a reaction buffer, and the like.
  • the invention also relates to antibodies specific for soluble truncated c-Met proteins, and additionally to reagents capable of detecting bound antibodies, such as labeled secondary antibodies, chromophores, enzymes and Provided is a kit for ELISA comprising a substrate thereof.
  • Kits for protein chips may include buffers, labeling reagents, wash buffers, and the like, used for hybridization.
  • kits exemplified above it includes several types of diagnostic kits that are made of a rapid diagnostic kit capable of detecting the markers of the present invention.
  • Plasma concentrations of soluble c-Met protein were performed by conventional methods using human c-Met (soluble) ELISA kits (Invitrogen Corporation, USA). 5 ⁇ l of each plasma sample was diluted using 495 ⁇ l of Standard Diluent Buffer and used for analysis. All samples were analyzed twice. A standard curve was used for each assay, which was made with a dilution of 50ng / ml standard of purified mouse myeloma-expressing recombinant protein. The concentration of the sample was determined by measuring the absorbance of the standard and the sample at 450 nm with a microplate reader.
  • the minimum detectable amount was ⁇ 0.5 ng / ml. This means that the average O.D. Obtained by adding to a value and calculating the corresponding concentration.
  • the ELISA kits were at concentrations of 4,000 to 50,000 pg / ml and were not cross reactive with other species.
  • the analysis procedure is as follows.
  • Plasma samples are stored at ⁇ 70 ° C. after analysis of the baseline until analysis. 495 ⁇ l of Standard Diluent Buffer is added to each tube containing 5 ⁇ l of plasma. After incubation at room temperature for 2 hours, the plate is washed four times with Wash buffer . 100 ⁇ l of biotin-bound anti-Hu c-Met solution is added to the wells. Shake the plate slowly at room temperature for 1 hour. After washing the plate four times, 100 ⁇ l of streptavidin-bound HRP Working Solution is added to the wells. The plate is incubated at room temperature for 30 minutes and then washed four times. 100 ⁇ l of Stabilized Chromogen is added to each well and incubated for 30 min at room temperature. 100 ⁇ l of Stop Solution was added to each well and incubated for 30 minutes, and enzyme linked immunosorbent assay (ELISA) was measured using a 450 nm wavelength with a microplate reader.
  • ELISA enzyme linked immunosorbent assay
  • H. pylori infection and CagA sera were measured using Helico Blot 2.1 TM (MP Biomedicals Asia Pacific, Singapore), an immunooblot assay.
  • Helico Blot 2.1 TM kits have been reported to have high sensitivity and accuracy
  • the analysis procedure is as follows.
  • Nitrocellulose strips were diluted using 2 ml Diluted wash buffer and incubated on a rocking platform at room temperature for 5 minutes. Plasma samples were stored at ⁇ 70 ° C. after baseline and before analysis. 2 ml of Blotting buffer was added to each well containing 2 ⁇ l of patient serum or positive / negative control. After incubation on a rocking platform at room temperature for 1 hour, the plates were washed three times using 2 ml of Diluted wash buffer , followed by soaking in the rocking platform for 5 minutes between each washing process. 2 ml of Working conjugate solution was added to the wells and incubated at room temperature for 1 hour. The conjugate was aspirated, washed three times, and 2 ml of Substrate solution was added. The plate was shaken at room temperature for 15 minutes and washed three times as above. Each strip has been interpreted by conventional standards and methods known to those skilled in the art.
  • the soluble c-Met protein optimum cut-off level was determined as a biomarker for gastric cancer diagnosis. Sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) were also calculated according to various cut-off levels.
  • Sensitivity and specificity are shown by true-positive rate ROC curves for false-positive rate.
  • AUC-ROC values of 0.90 to 1.0 indicate the best, 0.80 to 0.89 is good, 0.70 to 0.79 is normal, 0.60 to 0.69 is bad, and 0.50 to 0.59 are unavailable (Greiner M et al. , 2000).
  • the median age is 63.5 years old. Range is 40.0 to 83.0 years old
  • Past smokers are defined as current smokers.
  • Past drinkers are defined as current drinkers.
  • Table 5 shows the levels of soluble c-Met protein in plasma according to the above major risk factors for gastric cancer.
  • soluble c-Met protein levels were consistent in the patient group despite stratification according to age, sex, H. pylori infection, CagA serum response, and smoking status, which are known to be involved in gastric cancer. Appeared very low.
  • the median age of patients and controls is 64.0 years and ranges from 35.0 to 83.0 years.
  • c-Met protein levels are measured before and after the onset of gastric cancer, assuming that changes in the concentration of c-Met protein are also associated with gastric cancer progression. It was. Table 7 below relates to the measurement of c-Met protein levels before and after the onset of gastric cancer.
  • the mean concentration of soluble c-Met protein at 1 year before and after diagnosis of gastric cancer in developmental or diseased cases was 11.3 ng / ml, which was the minimum.
  • the mean concentration of soluble c-Met protein 5 years before and after the diagnosis of gastric cancer was similar or slightly lower than that of the control group (13.6 ng / ml vs. 13.7 ng / ml).
  • Optimal cut-off levels were determined by ROC analysis.
  • Table 10 shows the expected values when soluble c-Met protein levels are used as biomarkers for gastric cancer diagnostics in all (236) subjects.
  • AUC-ROC Model c-Met protein, CagA positivity, H. pylori infection, smoking status and total genetic score of seven CagA binding genes
  • the optimal cut-off values were determined by considering both the sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) together with the maximum AUC values calculated in the logistic model.
  • PV positive predictive values
  • NPV negative predictive values
  • soluble truncated c-Met protein which can be easily collected from blood, is used as a marker, and thus gastric cancer can be diagnosed easily and efficiently.

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Abstract

La présente invention concerne un procédé pour le diagnostic du cancer de l'estomac utilisant une protéine c-Met soluble tronquée, et plus particulièrement, un procédé pour le diagnostic du cancer de l'estomac comprenant une étape de mesure du taux d'une protéine c-Met soluble tronquée dans un spécimen biologique, et une étape de comparaison du taux de la protéine au taux de la protéine dans un organisme normal, et une composition incluant une formulation qui mesure le taux de la protéine c-Met soluble tronquée pour le diagnostic du cancer de l'estomac. Selon la présente invention, le cancer de l'estomac peut être diagnostiqué de manière adéquate et efficace juste en mesurant le taux de la protéine c-Met soluble tronquée dans le sang.
PCT/KR2011/008314 2010-11-02 2011-11-02 Procédé pour le diagnostic du cancer de l'estomac Ceased WO2012060636A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105431738A (zh) * 2013-04-05 2016-03-23 延世大学校产学协力团 胃癌的预后预测模型的建立方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101504818B1 (ko) * 2013-04-05 2015-03-24 연세대학교 산학협력단 위암에 대한 예후 예측 시스템
KR102184316B1 (ko) * 2019-10-25 2020-12-01 박선민 개인별 단일염기 다형성 정보에 따른 질병예측 프로그램 및 맞춤형 영양정보 제공방법

Non-Patent Citations (4)

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Title
HORI ET AL.: 'Expression of hepatocyte growth factor and c-met receptor in gastric mucosa during gastric ulcer healing. Scand.' J. GASTROENTEROL. vol. 35, no. 1, 2000, *
KNUDSEN ET AL.: 'A novel multipurpose monoclonal antibody for evaluating human c-MET expression in preclinical and clinical settings.' APPL. IMMUNOHISTOCHEM. MOL. MORPHOL. vol. 17, no. 1, January 2009, *
WANG ET AL.: 'Alterations of APC, c-met and p53 genes in tumor tissue and serum of patients with gastric cancers.' JOURNAL OF SURGICAL RESEARCH vol. 120, 2004, *
YANG, JAE JEONG: 'Candidate genes related to CagA signal transduction pathway and soluble c-Met protein as susceptible biomarkers for gastric cancer risk : a nested case-control study.' DOCTORAL DISSERTATION August 2010, *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105431738A (zh) * 2013-04-05 2016-03-23 延世大学校产学协力团 胃癌的预后预测模型的建立方法

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