WO2015080490A1 - Genetic marker or use thereof for predicting risk of colon cancer onset - Google Patents
Genetic marker or use thereof for predicting risk of colon cancer onset Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
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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
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- the present invention is a method for predicting the risk of colorectal cancer by identifying a specific monobasic polymorphism (SNP; base) that has a significant correlation with the risk of colorectal cancer.
- SNP monobasic polymorphism
- the present invention relates to a composition for predicting the risk of colorectal cancer, including a polynucleotide, a polypeptide, an antibody, or a cDNA, and a microarray and a kit including the same.
- the structure of the large intestine refers to an organ that starts from the end of the small intestine to the anus and is about 1.5m long.
- the large intestine consists of ascending, transverse, descending, sigmoid colon, rectum and anus.
- the major functions of the large intestine are digested and leftovers from the small intestine to absorb moisture and electrolytes and to discharge the remaining residue.
- Colorectal cancer is a malignant tumor of the ascending colon, transverse colon, descending colon, sigmoid colon and rectal mucosa. Lymph cancer, sarcoma, squamous cell carcinoma, etc. are included, but adenocarcinoma occurs with a high specific gravity. It is known that the incidence of colorectal cancer in each region in Korea is 25% for ascending colon and s phase colon, and 20% for rectum.
- Rectal cancer one of colorectal cancers, is the third most common cancer reported (1st; lung cancer, 2nd; gastric cancer, 3rd; rectal cancer).
- MCIJ Monitoring of Cancer Incidence in Japan
- men stomach cancer; 55.3 / 100,000
- colon cancer 45.1 / 100,000
- colorectal cancer is the most effective method of treatment, with survival rates ranging from early stage 1 to stage 3 70-90%, but survival rate 15% in the last 4 stages.
- the first is environmental factors, such as old age, excessive meat intake, fiber intake, lack of vitamin intake, lack of chestnut intake, lack of exercise, drinking, smoking.
- environmental factors such as old age, excessive meat intake, fiber intake, lack of vitamin intake, lack of chestnut intake, lack of exercise, drinking, smoking.
- genetic factors are known to involve several genes such as APC, KRAS, ⁇ 53, MLH1, MSH2, ⁇ 4 ⁇ and SMAD4 in various stages of cancer development and metastasis.
- SNP single nucleotide polymorphism
- GWAS full-length genome research
- G S generally proceeds with the assumption that co-on disease is associated with a common variant.
- Phenotype is an unexplained phenomenon. The view is determined by the combination of genotypes. Recently, gene-environmental interactions and gene-genetic interaction analysis have been widely used to compensate for this.
- the present inventors hypothesized that individual SNP mutations affect the risk of colorectal cancer, and analyzed the association between colorectal cancer risk and SNPs in clinical samples of colorectal cancer patients and normal people. We found a single SNP biomarker with predictable risk. Furthermore, the present inventors have completed the present invention by constructing a more robust colorectal cancer prediction model through gene-gene interaction analysis using a single SNP.
- One object of the present invention is to provide a method for predicting the risk of developing colorectal cancer by identifying specific SNP bases that have a significant correlation with colorectal cancer risk for gene samples obtained from patients.
- One object of the present invention is to provide a method for providing information for predicting the risk of colorectal cancer by identifying specific SNP bases that have a significant correlation with colorectal cancer risk for gene samples obtained from patients.
- Another object of the present invention is to provide a composition for predicting the risk of colorectal cancer, comprising a polynucleotide, a polypeptide or a cDNA thereof capable of identifying a specific SNP marker.
- Another object of the present invention is to provide a microarray for predicting the risk of colorectal cancer, including a polynucleotide, a polypeptide, an antibody thereto or a cDNA thereof capable of identifying a specific SNP marker.
- Another object of the present invention is to identify specific SNP markers It provides a kit for predicting the risk of colorectal cancer, comprising a polynucleotide, a polypeptide, an antibody thereto or a cDNA thereof.
- the present invention can provide information that can be diagnosed, predicted and prevented early in the colon cancer risk group by providing a genotype that is susceptible to colorectal cancer.
- the present invention may provide a method for providing information for developing and predicting a composition diagnostic kit for early diagnosis that can prevent colon cancer.
- . 2 shows the correlation between rs3865188 and rs3774261 and the adiponectin levels in human blood.
- rs3865188 M and rs3774261: M genotype combination group (median adiponectin in blood: 7.835 ug / ml) showing the highest risk for colorectal cancer.
- Adiponectin level was low (significance level).
- Colon cancer is caused by environmental and genetic factors, and predicting and preventing genetic factors can effectively prevent colon cancer.
- a powerful model for predicting colon cancer using gene-gene.interaction is presented.
- the present inventors confirmed the association between SNP (rs3865188) in the T-cadherin gene and the risk of colorectal cancer in 325 patients with colorectal cancer and 977 normal groups. Furthermore, the SNP in the adiponectin gene, which is a ligand of rs3865188 and T-cadherin, was identified. We analyzed the relationship between the interaction between the two groups (rs2241767, rs3821799, rs3774261, rs6773957) and the risk of colorectal cancer.
- rs3865188 is a single SNP to predict colorectal cancer risk. It was confirmed that a combination of rs3865188 and adiponectin SNP could predict a risk group up to 4.257 times higher. It was also confirmed that this gene-gene combination correlates with the actual amount of adiponectin in the blood.
- the present invention includes the step of identifying the polymorphism of the 27th base of the sequence represented by SEQ ID NO: 1 (NCBI refSNP ID: rs3865188) in the T-cadherin gene for a gene sample obtained from a patient It provides a method for providing information for predicting the risk of developing colorectal cancer.
- the present invention provides a polymorphism of the 27th base of the sequence represented by SEQ ID NO: 2 (NCBI refSNP ID: rs2241767) in the adiponect in gene for a gene sample obtained from a patient, and SEQ ID NO: 3 (in the adiponectin gene).
- NCBI refSNP ID: rs3821799) Polymorphism of the 27th base of the sequence, SEQ ID NO: 4 in the adiponectin fusion (NCBI refSNP ID:
- rs3774261 polymorphism of the 27th base of the sequence, and adiponectin gene .
- Providing information for predicting the risk of colorectal cancer further comprising the step of identifying one or more polymorphisms selected from the group consisting of the polymorphism of the 27th base of the sequence represented by SEQ ID NO: 5 (NCBI refSNP ID: rs6773957) Provide a method.
- T-cadher in (T-cadher in, H-cadher in or CDH13) is also known as a receptor for adiponectin and LDL, and methylation studies of the T. cadherin promoter region in relation to colorectal cancer have been reported. (Br J Cancer, 2004, 90, 1030-3, Cancer Res, 2002, 62 (12) 3383-6).
- adiponectin (adiponect in, APN, adipoQ or apMl) has been reported to correlate with body fat and insulin resistance, and lower levels of adiponectin in relation to colorectal cancer are associated with colorectal cancer (J Nat l Cancer Inst , 2005, 97, 1688-94, int J Colorectal Dis, 2009, 24, 275-81).
- Table 1 below shows the NCBI refSNP ID for the SNP marker provided by the present invention, the sequence of the SNP and its position. Those skilled in the art can easily identify the position and sequence of the SNP using the number. The specific sequence corresponding to the refSNP ID of the SNP registered in the NCBI will continue. Depending on the results of the study of the gene may be slightly changed, it will be apparent to those skilled in the art that such altered sequences are also included within the scope of the present invention.
- the case where the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the Tischadd Herrin gene is TT may be predicted to have a higher risk of colorectal cancer than M or AT.
- the rs3865188: ⁇ genotype was 1.577 times higher in risk than the rs3865188: M or rs3865188: AT. Genotype group. .
- the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the T-cadherin gene is ⁇ and the genotype of the 27th base of SEQ ID NO: 2 (rs2241767) in the adiponectin gene is M.
- the genotype of the 27th base of SEQ ID NO: 1 is TT and the genotype of the 27th base of SEQ ID NO: 2 is GA or M, it may be predicted that the risk of colon cancer is high.
- rs3865188: TT and rs2241767: AA genotypes was 2.485 times more susceptible to colorectal cancer than the rs3865188: AA and rs2241767: GG genotypes.
- rs3865188: AA and rs2241767: compared to GG genotypes rs3865188: TT and rs2241767: GA and AA genotypes were associated with risk for colon cancer. It was confirmed that the sensitivity is 2.3 times higher.
- the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the T-cadherin gene is ⁇ and the genotype of the 27th base of SEQ ID NO: 3 (rs2241767) in the adiponectin gene is CC.
- the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the T-cadherin gene in the present invention is ⁇ , and the 27th base of SEQ ID NO: 4 (rs3774261) in the adiponected gene. This GG can be expected to increase the risk of colon cancer.
- rs3865188 TT.
- rs3774261 GG genotypes was 4.257 times more susceptible to risk of colorectal cancer than the rs3865188: AA and rs3774261: AA genotypes.
- the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the T-cadherin gene is ⁇
- the genotype of the 27th base of SEQ ID NO: 5 (rs6773957) of adiponectin genesis is GG. Can be expected to be at high risk for colorectal cancer.
- the patient may be a general patient before the onset of colorectal cancer, and may be a patient to predict and manage the risk of colorectal cancer. Alternatively, the patient may have already developed colorectal cancer.
- a sample obtained from a patient includes tissue, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid ⁇ or urine, etc., and obtain a genetic sample from these samples, the genetic sample is DNA, mRNA, or mRNA CDNA synthesized from.
- the term "prediction" means that colorectal cancer will develop in a patient. This is to determine whether there is a possibility, whether the colorectal cancer is relatively high, or whether colorectal cancer has already occurred.
- the method of the present invention is a patient at high risk of developing colorectal cancer for any particular patient and can be used to prevent or delay the onset of the disease through special and appropriate management.
- the methods of the present invention can be used clinically to make treatment decisions by early diagnosis of colorectal cancer and selecting the most appropriate treatment regimen.
- polymorphi sm refers to a case in which two or more alleles exist in one locus. It is called s ingl e nucleotide polymorphism (SNP). Preferred polymorphic markers have two or more alleles which exhibit an incidence of at least 1%, more preferably at least .10% or at least 20% in the selected population.
- al lele refers to several types of genes that exist at the same locus of homologous chromosomes. Alleles are also used to indicate polymorphism, for example SNPs have two alleles (bi al el e).
- the present invention provides a composition for predicting the risk of developing colorectal cancer in a patient.
- the composition is characterized by containing a reagent for identifying the 27th base of the sequence represented by SEQ ID NO: UNCBI refSNP ID: rs3865188) in the Tischadd Harin gene with respect to the genetic sample isolated from the patient.
- the reagent contained in the composition of the present invention is preferably a poly consisting of 10 or more consecutive bases including the 27th base of the sequence represented by SEQ ID NO: KNCBI refSNP ID: rs3865188 in the Tibucatherin gene. Nucleotides or complementary polynucleotides thereof
- composition is represented by the 27th base of the sequence represented by the asterisk number 2 (NCBI refSNP ID: rs2241767) in the adiponectin gene, SEQ ID NO: 30 BI refSNP ID: rs3821799) in the adiponectin gene for the gene sample isolated from the patient Of the adiponectin gene, the 27th base of the sequence One selected from the group consisting of the 27th base of the sequence represented by SEQ ID NO: 4 (NCBI refSNP ID: rs3774261), and the 27th base of the sequence represented by SEQ ID NO: 5 ( NCB I re fSNP ID: rs6773957) in the adiponectin gene It may further include a reagent for identifying the above base.
- the reagent contained in the composition is the 27th base of the sequence represented by SEQ ID NO: 2 (NCBI refSNP ID: rs2241767) in the adiponectin gene, and the sequence represented by SEQ ID NO: 30 BI refSNP ID: rs3821799 in the adiponectin gene).
- 27th base group consisting of the 27th base of the sequence represented by SEQ ID NO: 40 BI refSNP 10: rs3774261) in the adiponectin gene and the 27th base of the sequence represented by SEQ ID NO: 5 (NCBI refSNP ID: rs6773957) in the adiponectin gene It may further comprise a polynucleotide consisting of 10 or more consecutive bases comprising one or more bases selected from or complementary polynucleotides thereof.
- the present invention provides the polynucleotide in one aspect.
- the polynucleotide according to the present invention or its complementary polynucleotide may be composed of 10 or more, preferably 10 to 100, more preferably 20 to 60, even more preferably 40 to 60 consecutive bases. have.
- polymorphic c sequences Said polynucleotides or their complementary polynucleotides according to the invention are polymorphic c sequences.
- the polymorphic sequence refers to a sequence comprising a polymorphic site (polymorphi c si te) that represents a monobasic polymorphism in the nucleotide sequence.
- a polymorphic site refers to a site where a monobasic polymorphism occurs in the polymorphic sequence.
- the polynucleotide may be DNA or R A.
- the reagent contained in the composition of the present invention may preferably include a polynucleotide which specifically hybridizes with the polynucleotide or its complementary polynucleotide.
- the present invention relates to a polynucleotide that specifically hybridizes with the polynucleotide or its complementary polynucleotide. It provides as an aspect.
- the polynucleotide that specifically hybridizes with the polynucleotide or its complementary polynucleotide is an all lele-speci fic polynucleotide.
- Allele specific polynucleotide means to specifically hybridize to each allele. In other words, it refers to the hybridization so that the bases of the polymorphic sites present in the polymorphic sequence can be specifically distinguished.
- localization can usually be carried out under stringent conditions, for example salt concentrations below 1 M and temperatures above 25.
- the allele specific polynucleotide may be an allele specific probe.
- the probe means a hybridization probe, and refers to a ligonucleotide capable of sequence-specific binding to the complementary strand of a nucleic acid.
- Allele-specific probes have polymorphic sites in nucleic acid fragments derived from two individuals of the same species, which are common to DNA fragments derived from one individual but not to fragments derived from other individuals. In this case, the conditions for homogenization should be strict enough to only localize to one of the alleles, showing a significant difference in the intensities of alleles.
- the central region is preferably aligned with the polymorphic region of the polymorphic sequence. This can lead to good localization differences between different allelic forms.
- the probe of the present invention can be used in diagnostic kits or prediction methods such as microarrays for detecting alleles and predicting the risk of colorectal cancer.
- the allele specific polynucleotide may be an allele specific primer.
- Appropriate length of the primer may vary depending on the intended use, but generally consists of 15 to 30 bases.
- the primer sequence need not be completely complementary to the template but must be sufficiently complementary to hybridize with the template.
- the primer amplifies a DNA fragment comprising the polymorphic site by generalizing to a DNA sequence comprising the polymorphic site.
- the primer of the present invention can be used in diagnostic kits or prediction methods such as microarrays for detecting alleles and predicting the risk of colon cancer.
- the reagent contained in the composition of the present invention may include a polypeptide encoded by the polynucleotide or its complementary polynucleotide.
- the present invention provides, as an aspect, a polypeptide encoding the polynucleotide.
- polypeptides may be used in compositions, microarrays or kits for predicting colorectal cancer risk.
- antibodies to the polypeptide can be used in place of the polypeptide.
- an antibody means a specific protein molecule directed to an antigenic site as a term known in the art.
- antibody means an antibody that specifically binds to a polypeptide comprising the SNP marker of the present invention.
- Such an antibody is cloned into an expression vector according to a conventional method to obtain a protein encoded by the marker gene, and can be prepared by a conventional method from the obtained protein. It also includes partial peptides that can be made from an elevated protein, and the partial peptide of the present invention includes at least 7 amino acids, preferably 9 amino acids, more preferably 12 or more amino acids.
- the form of the antibody of the present invention is not particularly limited and a part thereof is included in the antibody of the present invention and all immunoglobulin antibodies are included as long as they are polyclonal antibody, monoclonal antibody or antigen-binding agent.
- the antibodies of the present invention also include humanized antibodies and special antibodies. Included.
- Antibodies used in the detection of markers for predicting the risk of colorectal cancer onset of the present invention include functional fragments of antibody molecules as well as complete forms having two full length light chains and two full length heavy chains.
- the functional fragment of an antibody molecule means the fragment which has at least antigen binding function, and includes Fab, F (ab '), F (ab') 2, and Fv.
- the polynucleotide of the present invention, the polynucleotide specifically hybridizing thereto, or the polypeptide specifically encoded by the polynucleotide thereof or the cDNA thereof may also be used for the preparation of a microarray or kit for predicting colorectal cancer risk. It is provided for use.
- the microarray or kit may be prepared by conventional methods known to those skilled in the art. Can be manufactured.
- the microarray is a conventional microarray except that the polynucleotide, polypeptide, cDNA and the like of the present invention. Can be done. Detection of nucleic acid on the microarray and the results of the localization are well known in the art, wherein the detection is for example detectable nucleic acid samples comprising fluorescent materials, for example, substances such as Cy3 and Cy5. The labeling result can be detected by labeling with a labeling substance capable of generating a signal, then by waving on a microarray and detecting a signal generated from the labeling substance.
- the kit may include not only polynucleotides, polypeptides, cDNAs, etc. of the present invention but also one or more other component compositions, solutions, or devices suitable for analytical methods.
- the kit of the present invention may be a kit containing the necessary elements necessary to perform PCR, test tubes or other suitable containers, semiperiods (pH and magnesium concentrations vary), deoxynucleotides (dNTPs) Enzymes such as Taq-polymerase and reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, and sterile water.
- the kit of the present invention may be a kit for predicting colorectal cancer risk including essential elements necessary for performing a DNA chip, and the DNA chip cart is attached to a polynucleotide, primer or probe specific for the SNP.
- the substrate may comprise a nucleic acid corresponding to the quantitative control gene or fragment thereof.
- Identification of the genotype of the SNP of the present invention sequencing analysis, sequencing analysis using an automatic base sequence analyzer, pyrose sequencing, microarray shake, PCR-RELP method (restriction fragment length polymorphism), PCR ⁇ SSCP method single strand conformation polymorphism (PCR), PCR-SS0 method (specific sequence oligonucleotide), PCR-SS0 method and dot hybridization method combined AS0 (allele specific oligonucleotide) hybridization method, TaqMan-PCR method, MALDI—T0F / MS method, RCA method (rolling circle amplification), HRM (high resolution melting) method, primer extension method, Southern It can be performed by a well-known method, such as a blot hybridization method and a dot hybridization method.
- results of the SNP polymorphism can be statistically processed using statistical analysis methods commonly used in the art, for example, Student's t-test, chi-square test ( consecutive, such as obtained by the Chi-square test), a linear regression analysis (linear regression line analysis), multivariate logistic regression analysis (multiple logistic regression analysis). Analysis can be performed using variables such as continuous variables, categorical variables, odds ratio, and 95% confidence interval.
- sample collection was performed using a colorectal cancer sample in the metabolic syndrome cohort of the Yonsei University Underground Research Team, and the adiponectin blood level was used for the media adiponectin ELISA kit.
- the following statistical analysis tool was used for the present invention.
- T-test and AN0VA were used according to the normality test, and other nonparametric tests were used for statistical analysis.
- Gene-gene interactions were basically analyzed by logistic regression and corrected for age and body mass coefficients.
- Example 2 Population Configuration for Analyzing SNP-SNP Interaction For the present invention, 325 patients with colorectal cancer and a normal group in the group used in the metabolic syndrome cohort study by the Underground Research Team at Yonsei University Health School
- the adiponectin gene SNPs were rsl82052, rs 17366568, rs2241767, rs3821799, rs3774261, and rs6773957.
- the association disparity was analyzed using Haploview v4.2 based on the genotype data of the Korean cohort reported by Yonsei University.
- adiponectin SNP was not found to be associated with colorectal cancer.
- the gene-genetic interaction between rs3865188 SNP and adiponectin SNP of T-cadherin was analyzed.
- rs3865188 M and rs2241767: GG genotype rs3865188: TT and rs2241767: AA genotype Those who had a susceptibility to colorectal cancer were 2.485 times higher.
- the second SNP of rs3821799 in the LD block of adiponectin was also confirmed to be in combination with rs3865188.
- the sensitivity to colorectal cancer was found to be 3.573 times higher (Table 6).
- Rs3774261 the third SNP of the adiponectin LD block, was identified as the strongest of the six SNPs in combination with rs3865188.
- Rs6773957 the last SNP of the adiponectin LD block, can be identified in combination with rs3865288.
- the rs3865188 found by the present inventors can predict the risk alone, but the combination of rs3865188 and four SNPs in which the LD block of adiponectin is formed can be further refined and predict the high risk group.
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Abstract
The present invention relates to a method for predicting the risk of colon cancer onset by identifying certain single nucleotide polymorphism (SNP) bases having a significant correlation with the risk of colon cancer onset, a composition including a polynucleotide, a polypeptide, an antibody or cDNA which can identify the SNP for predicting the risk of colon cancer onset, and a microarray and a kit including the composition.
Description
【명세서】 【Specification】
[발명의 명칭】 [Name of invention]
대장암 발병 위험도 예측을 위한 유전 마커와 이의 이용 【기술분야】 Genetic Markers and Their Uses to Predict the Risk of Colorectal Cancer
본 발명은 대장암 발병 위험도와 유의적 상관관계를 가지는 특정 단일염기다형성 (SNP; singl e nuc leot i de polymorphi sm) 염기를 확인하여 대장암 발병 위험도를 예측하는 방법， 상기 SNP를 확인할 수 있는 The present invention is a method for predicting the risk of colorectal cancer by identifying a specific monobasic polymorphism (SNP; base) that has a significant correlation with the risk of colorectal cancer.
폴리뉴클레오티드， 폴리펩티드， 항체 또는 cDNA를 포함하는 대장암 발병 위험도 예측용 조성물， 그리고 이를 포함하는 마이크로어레이 및 키트에 관한 것이다. The present invention relates to a composition for predicting the risk of colorectal cancer, including a polynucleotide, a polypeptide, an antibody, or a cDNA, and a microarray and a kit including the same.
【배경 기술】 [Background technology]
대장의 구조는 소장 끝에서부터 시작하여 항문에 이르는 장기를 말하며， 길이는 약 1.5m정도이다. 대장은 상행， 횡행， 하행， S자 결장， 직장 그리고 항문으로 구성하고 있으며， 대장의 주요 기능은 소화되고 남은 음식물을 소장으로부터 받아 수분과 전해질을 흡수하고 나머지 찌꺼기를 배출하는 기능을 한다. The structure of the large intestine refers to an organ that starts from the end of the small intestine to the anus and is about 1.5m long. The large intestine consists of ascending, transverse, descending, sigmoid colon, rectum and anus. The major functions of the large intestine are digested and leftovers from the small intestine to absorb moisture and electrolytes and to discharge the remaining residue.
대장암은 상행결장， 횡행결장， 하행결장， S자 결장 그리고 직장 점막에 발생하는 악성종양으로 선암,. 림프암， 육종， 편평 상피암 등이 포함되나 이중 선암 (adenocarcinoma)이 높은 비중으로 발생한다. 우리나라 부위별 대장암 발생 빈도는 상행결장과 s상 결장이 각각 25%를 차지하며 직장이 20%를 차지하는 것으로 알려져 있다. Colorectal cancer is a malignant tumor of the ascending colon, transverse colon, descending colon, sigmoid colon and rectal mucosa. Lymph cancer, sarcoma, squamous cell carcinoma, etc. are included, but adenocarcinoma occurs with a high specific gravity. It is known that the incidence of colorectal cancer in each region in Korea is 25% for ascending colon and s phase colon, and 20% for rectum.
대한민국 대장암을 살펴보면 70년대 이전에는 흔하게 발생하는 질환이 아니었지만 서구화된 식생활의 변화로 현재 점점 증가하는 추세이다. 통계청 사망원인 통계 (국가승인통계 제 10154호)와 보건복지부 암 등록 통계 (국가승인통계 11744호)에 따르면 2000년부터 2010년까지의 10년 사이에， '대장암 발생률은 10만 명 중 21.8명에서 41.5명으로， 사망를은 10만 명 중 8.8명에서 15.4명으로 거의 두 배로 증가하였으며 여전히 증가 추세이다. 그리고 대한민국과 인접한 아시아 국가 중 중국과 일본을 살펴보면，
중국 매체를 인용한 미국 자유아시아방송 (RFA)보도에서 중국종양등록센터가 발간한 <2013년 중국 종양 연간 보고서 >에서 암사망자수가 연간 270만명에 이르며， 연간 평균 312만명이 암 확진 판정을 받고 있으나 매년 증가하는 추세이다. 그리고 대장암의 하나인 직장암이 전체 암 중 3번째로 많이 발생하는 것으로 보고 되었다 (1위; 폐암, 2위; 위암, 3위; 직장암). 일본의 경우도 2006년 Monitoring of Cancer Incidence in Japan(MCIJ)에 의한 통계 자료에 의하면 남성 (위암 ;55.3명 /10만명， 대장암 ;45.1명 /10만명， Looking at colon cancer in Korea, it was not a common disease before the 70s, but it is increasing gradually due to changes in westernized diet. Statistics Cause of Death Statistics (approved by the state statistics No. 10154 No.) and the Department of Health and Human Services Cancer Registry statistics (approved by the state statistics, 11,744 calls) According to the ten years from 2000 to 2010, colorectal cancer was 21.8 people among 100,000 people Deaths nearly doubled from 8.8 to 15.4 out of 100,000, still increasing. And if you look at China and Japan among Asian countries adjacent to Korea, In the 2013 China Oncology Annual Report published by the China Center for Oncology (RFA), citing Chinese media, the number of cancer deaths reached 2.7 million people per year, with an average of 3.12 million people diagnosed with cancer. It is increasing every year. Rectal cancer, one of colorectal cancers, is the third most common cancer reported (1st; lung cancer, 2nd; gastric cancer, 3rd; rectal cancer). In Japan, according to statistics from the Monitoring of Cancer Incidence in Japan (MCIJ) in 2006, men (stomach cancer; 55.3 / 100,000, colon cancer: 45.1 / 100,000,
폐암； 41.6/10만명 )，여성 (유방암； 52/10만명，대장암； 25.6명 /10만명，위암； 20 · 3 /10만명) 각각 전체 암 중 2번째로 많이 발병하는 것으로 보고 Lung cancer; 41.6 / 100,000), women (breast cancer; 52 / 100,000, colorectal cancer; 25.6 / 100,000, stomach cancer; 20, 3 / 100,000)
되었다 (International Jounal of Cancer , 2014,134,747-754). (International Jounal of Cancer, 2014, 134,747-754).
- 현재 대장암은 다른 소화기 계통 암과 같이 외과적 수술이 가장 효과적인 치료 방법으로써, 1기 초기단계에서 3기까지 생존율이 70~90%의 생존율을 보이지만 마지막 4기에서는 15%로 생존율을 보인다. -As with other gastrointestinal cancers, colorectal cancer is the most effective method of treatment, with survival rates ranging from early stage 1 to stage 3 70-90%, but survival rate 15% in the last 4 stages.
대장암의 주요 위험요소는 크게 두 가지로 나눌 수 있다. 첫 번째는 환경적인 요소로서， 고령， 과도한 육류섭취, 섬유질 섭취부족, 비타민 섭취부족， 칼슴 섭취부족， 운동 부족， 음주， 흡연 등이 원인으로 알려져 있다. 두 번째는 유전학적 요소로서 암이 발달해서 전이까지 가는 여러 단계에는 APC, KRAS, Ρ53, MLH1, MSH2, ΙΝΚ4Α 및 SMAD4 등의 여러 유전자가 관여하는 것으로 알려져 있다. There are two major risk factors for colorectal cancer. The first is environmental factors, such as old age, excessive meat intake, fiber intake, lack of vitamin intake, lack of chestnut intake, lack of exercise, drinking, smoking. Second, genetic factors are known to involve several genes such as APC, KRAS, Ρ53, MLH1, MSH2, ΙΝΚ4Α and SMAD4 in various stages of cancer development and metastasis.
한편， 인간의 경우 약 1000염기당 1회 빈도로 변이가 있는데 이것을 On the other hand, in humans, there is a mutation at a frequency of about 1000 bases.
SNP (single nucleotide polymorphism)라고 하며, 5% 다형을 common polymorph ism이라고 하며， 1~5 다형을 rare polymorphism이라고 한다. 현재 인간의 전체 염기서열을 분석하기 위해 많은 실험 기법 등이 발달하였고, 그 중 전장 유전체 연구 (Genome-wide association study ： GWAS) 현재까지 많은 질환 연구에 사용 되고 있다. It is called single nucleotide polymorphism (SNP), 5% polymorphism is called common polymorph ism, and 1 ~ 5 polymorphism is called rare polymorphism. Currently, many experimental techniques have been developed to analyze human nucleotide sequences. Among them, full-length genome research (GWAS) has been used for many disease studies.
G S는 일반적으로 co醒 on disease는 common variant와 연관되어 있다는 가정 하에 연구를 진행하는데 이러한 연구에서 '손실된 G S generally proceeds with the assumption that co-on disease is associated with a common variant.
유전율 (missing heritability) 1 의 문제가 발생하는 것으로 생각된다. It is thought that a problem of permitting heritability 1 occurs.
'손실된 유전율' 이란 개별유전자가 질환이나 행동 등의 Lost permittivity means that an individual gene can
표현형 (phenotype)을 모두 설명할 수 없어 나타나는 현상이며 , 질환은 모든
유전자형의 조합에 의해 결정된다는 견해이다. 최근에는 이를 보완하기 위해 유전자 -환경 상호작용， 유전자-유전자 상호작용 분석 등이 많이 활용하고 있다. Phenotype is an unexplained phenomenon. The view is determined by the combination of genotypes. Recently, gene-environmental interactions and gene-genetic interaction analysis have been widely used to compensate for this.
그러나， 종래에는 유전자 SNP 다형성을 이용하여 대장암의 위험도를 진단하기 위한 연구는 거의 보고되지 않았다. However, in the past, few studies have been used to diagnose the risk of colorectal cancer using gene SNP polymorphism.
【발명의 상세한 설명】 [Detailed Description of the Invention]
【기술적 과제】 [Technical problem]
이에， 본 발명자들은 개개인의 SNP 변이가 대장암 발병 위험도에 영향을 미칠 것으로 가설을 세우고， 대장암 환자들과 정상인들의 임상 시료 내 SNP 들과 대장암 위험도와의 연관성을 분석한 결과, 대장암 발병 위험을 예측할 수 있는 단일 SNP 바이오마커를 찾아내었다. 나아가， 본 발명자들은 단일 SNP 를 이용한 유전자-유전자 상호작용 분석을 통하여， 보다 강력한 대장암 예측 모형을 구축하여 본 발명을 완성하게 되었다. Therefore, the present inventors hypothesized that individual SNP mutations affect the risk of colorectal cancer, and analyzed the association between colorectal cancer risk and SNPs in clinical samples of colorectal cancer patients and normal people. We found a single SNP biomarker with predictable risk. Furthermore, the present inventors have completed the present invention by constructing a more robust colorectal cancer prediction model through gene-gene interaction analysis using a single SNP.
【기술적 해결방법】 Technical Solution
본 발명의 하나의 목적은 환자로부터 얻은 유전자 시료에 대하여 대장암 위험도와 유의적 상관관계를 갖는 특정의 SNP 염기를 확인함으로써， 대장암 발병 위험도를 예측하는 방법을 제공하는 것이다. One object of the present invention is to provide a method for predicting the risk of developing colorectal cancer by identifying specific SNP bases that have a significant correlation with colorectal cancer risk for gene samples obtained from patients.
본 발명의 하나의 목적은 환자로부터 얻은 유전자 시료에 대하여 대장암 위험도와 유의적 상관관계를 갖는 특정의 SNP 염기를 확인함으로써, 대장암 발병 위험도를 예측하기 위한 정보를 제공하는 방법을 제공하는 것이다. One object of the present invention is to provide a method for providing information for predicting the risk of colorectal cancer by identifying specific SNP bases that have a significant correlation with colorectal cancer risk for gene samples obtained from patients.
본 발명의 다른 하나의 목적은 특정의 SNP 마커를 확인할 수 있는 폴리뉴클레오티드， 폴리펩티드 또는 그의 cDNA를 포함하는， 대장암 발병 위험도 예측용 조성물을 제공하는 것이다. Another object of the present invention is to provide a composition for predicting the risk of colorectal cancer, comprising a polynucleotide, a polypeptide or a cDNA thereof capable of identifying a specific SNP marker.
본 발명의 다른 하나의 목적은 특정의 SNP 마커를 확인할 수 있는 폴리뉴클레오티드， 폴리펩티드， 이에 대한 항체 또는 이의 cDNA를 포함하는， 대장암 발병 위험도 예측용 마이크로어레이를 제공하는 것이다. Another object of the present invention is to provide a microarray for predicting the risk of colorectal cancer, including a polynucleotide, a polypeptide, an antibody thereto or a cDNA thereof capable of identifying a specific SNP marker.
본 발명의 다른 하나의 목적은 특정의 SNP 마커를 확인할 수 있는
폴리뉴클레오티드， 폴리펩티드， 이에 대한 항체 또는 이의 cDNA를 포함하는， 대장암 발병 위험도 예측용 키트를 제공하는 것이다. Another object of the present invention is to identify specific SNP markers It provides a kit for predicting the risk of colorectal cancer, comprising a polynucleotide, a polypeptide, an antibody thereto or a cDNA thereof.
【유리한 효과】 Advantageous Effects
본 발명은 대장암에 걸리기 쉬운 유전자형을 제공함으로써 대장암 위험군을 조기에 진단， 예측하여 예방 할 수 있는 정보를 제공 할 수 있다. 또한， 본 발명은 대장암을 예방 할 수 있는 조기 진단용 조성물 진단 키트 개발 및 예측을 위한 정보 제공 방법을 제공 할 수 있다. 【도면의 간단한 설명】 The present invention can provide information that can be diagnosed, predicted and prevented early in the colon cancer risk group by providing a genotype that is susceptible to colorectal cancer. In addition, the present invention may provide a method for providing information for developing and predicting a composition diagnostic kit for early diagnosis that can prevent colon cancer. [Brief Description of Drawings]
도 1은 6개의 아디포넥틴 유전자 SNP간의 연관불균형 (LD)을 1 shows the linkage disequilibrium (LD) between the six adiponectin genes SNPs.
나타낸다. Indicates.
. 도 2는 rs3865188과 rs3774261 간의 상호 작용과 인간 혈액 내 아디포넥틴 수치와의 상관관계를 나타낸다. rs3865188 : M 와 rs3774261 : M 유전자형 조합군 (혈중 아디포넥틴 중앙값: 7.835ug/ml )에 비하여 대장암에 대해 가장 높은 위험도를 나타낸 rs3865188 : ΊΤ 와 rs3774261 : GG유전자형 조합군 (아디포넥틴 수치 중앙값: 4.800ug/ml )의 혈중 아디포넥틴 양이 적었다 (유의수준 ) .0017) . 【발명의 실시를 위한 최선의 형태】 . 2 shows the correlation between rs3865188 and rs3774261 and the adiponectin levels in human blood. rs3865188: M and rs3774261: M genotype combination group (median adiponectin in blood: 7.835 ug / ml) showing the highest risk for colorectal cancer. Adiponectin level was low (significance level). [Best form for implementation of the invention]
대장암은 환경적인 요인과 유전적인 요인에 기인하는데 유전적인 요인을 미리 예측하여 예방하는 것이 대장암을 효과적으로 예방할 수 있다. 본 발명에서는 유전자-유전자.상호작용을 이용하여 대장암을 예측하는 강력한 모형을 제시하였다. Colon cancer is caused by environmental and genetic factors, and predicting and preventing genetic factors can effectively prevent colon cancer. In the present invention, a powerful model for predicting colon cancer using gene-gene.interaction is presented.
본 발명자들은 대장암 환자 325명과 정상군 977명을 대상으로 티-캐드헤린 유전자 중의 SNP (rs3865188)와 대장암 위험도 간의 연관성을 확인하였고， 나아가 및 rs3865188과 티 -캐드헤린의 리간드인 아디포넥틴 유전자 중의 SNP들 (rs2241767 , rs3821799 , rs3774261 , rs6773957)간의 상호작용과 대장암 위험도 간의 연관성을 분석하였다. The present inventors confirmed the association between SNP (rs3865188) in the T-cadherin gene and the risk of colorectal cancer in 325 patients with colorectal cancer and 977 normal groups. Furthermore, the SNP in the adiponectin gene, which is a ligand of rs3865188 and T-cadherin, was identified. We analyzed the relationship between the interaction between the two groups (rs2241767, rs3821799, rs3774261, rs6773957) and the risk of colorectal cancer.
그 결과， rs3865188 는 단일 SNP로서 대장암 위험도를 예측하는 데
사용할 수 있고， 나아가 rs3865188와 아디포넥틴 SNP의 조합에 의해서는 최고 4.257배 높은 위험군이 예측될 수 있음이 확인되었다. 또한 이러한 유전자-유전자 조합이 실제 혈액 내 아디포넥틴 양과 상관성이 있음을 확인 할 수 있었다. As a result, rs3865188 is a single SNP to predict colorectal cancer risk. It was confirmed that a combination of rs3865188 and adiponectin SNP could predict a risk group up to 4.257 times higher. It was also confirmed that this gene-gene combination correlates with the actual amount of adiponectin in the blood.
이에, 하나의 양태로서， 본 발명은 환자로부터 얻은 유전자 시료에 대하여， 티-캐드헤린 유전자 중의 서열번호 1(NCBI refSNP ID : rs3865188)로 표시되는 서열의 27번째 염기의 다형성을 확인하는 단계를 포함하는， 대장암 발병 위험도를 예측하기 위한 정보를 제공하는 방법을 제공한다. Thus, in one aspect, the present invention includes the step of identifying the polymorphism of the 27th base of the sequence represented by SEQ ID NO: 1 (NCBI refSNP ID: rs3865188) in the T-cadherin gene for a gene sample obtained from a patient It provides a method for providing information for predicting the risk of developing colorectal cancer.
바람직한 양태로서, 본 발명은 환자로부터 얻은 유전자 시료에 대하예 아디포넥틴 (adiponect in) 유전자 중의 서열번호 2(NCBI refSNP ID : rs2241767)로 표시되는 서열의 27번째 염기의 다형성， 아디포넥틴 유전자 중의 서열번호 3(NCBI refSNP ID : rs3821799)로 표시되는 서열의 27번째 염기의 다형성， 아디포넥틴 융전자 중의 서열번호 4(NCBI refSNP ID : In a preferred embodiment, the present invention provides a polymorphism of the 27th base of the sequence represented by SEQ ID NO: 2 (NCBI refSNP ID: rs2241767) in the adiponect in gene for a gene sample obtained from a patient, and SEQ ID NO: 3 (in the adiponectin gene). NCBI refSNP ID: rs3821799) Polymorphism of the 27th base of the sequence, SEQ ID NO: 4 in the adiponectin fusion (NCBI refSNP ID:
rs3774261)로 표시되는 서열의 27번째 염기의 다형성， 및 아디포넥틴 유전자 중의 .서열번호 5(NCBI refSNP ID : rs6773957)로 표시되는 서열의 27번째 염기의 다형성으로 이루어진 군에서 선택되는 하나 이상의 다형성을 확인하는 단계를 더욱 포함하는， 대장암 발병 위험도를 예측하기 위한 정보를 제공하는 방법을 제공한다. rs3774261) polymorphism of the 27th base of the sequence, and adiponectin gene . Providing information for predicting the risk of colorectal cancer further comprising the step of identifying one or more polymorphisms selected from the group consisting of the polymorphism of the 27th base of the sequence represented by SEQ ID NO: 5 (NCBI refSNP ID: rs6773957) Provide a method.
본 발명에서， 티-캐드헤린 (T-cadher in , H-cadher in또는 CDH13)은 아디포넥틴의 수용체이면서 LDL의 수용체로도 알려져 있으며， 대장암 관련하여 티ᅳ캐드헤린 프로모터 영역의 메틸화 연구가 보고되어 있다 (Br J Cancer , 2004 , 90， 1030-3 , Cancer Res , 2002 , 62( 12) 3383-6) . In the present invention, T-cadher in (T-cadher in, H-cadher in or CDH13) is also known as a receptor for adiponectin and LDL, and methylation studies of the T. cadherin promoter region in relation to colorectal cancer have been reported. (Br J Cancer, 2004, 90, 1030-3, Cancer Res, 2002, 62 (12) 3383-6).
또한， 아디포넥틴 (adiponect in, APN , adipoQ또는 apMl)은 체내 지방과 인술린 저항성 관련성이 보고되었으며， 대장암 관련하여 체내 아디포넥틴 수치가 낮을수록 대장암과의 연관성이 높다고 보고되었다 (J Nat l Cancer Inst , 2005 , 97 , 1688-94 , int J Colorectal Di s , 2009 , 24， 275-81) . In addition, adiponectin (adiponect in, APN, adipoQ or apMl) has been reported to correlate with body fat and insulin resistance, and lower levels of adiponectin in relation to colorectal cancer are associated with colorectal cancer (J Nat l Cancer Inst , 2005, 97, 1688-94, int J Colorectal Dis, 2009, 24, 275-81).
아래 표 1은 본 발명에서 제공하는 SNP 마커에 대한 NCBI의 refSNP ID는 해당 SNP의 서열 및 그 위치를 나타내는 것이다. 당업자라면 상기 번호를 이용하여 SNP의 위치 및 서열을 용이하게 확인할 수 있다. NCBI에 등록되어 있는 SNP의 refSNP ID에 해당하는 구체적인 서열은 계속되는
유전자에 대한 연구 결과에 따라 약간씩 변경될 수 있으며， 이러한 변경된 서열 또한 본 발명의 범위 내에 포함됨은 당업자에게 자명할 것이다. Table 1 below shows the NCBI refSNP ID for the SNP marker provided by the present invention, the sequence of the SNP and its position. Those skilled in the art can easily identify the position and sequence of the SNP using the number. The specific sequence corresponding to the refSNP ID of the SNP registered in the NCBI will continue. Depending on the results of the study of the gene may be slightly changed, it will be apparent to those skilled in the art that such altered sequences are also included within the scope of the present invention.
【표 11 Table 11
다른 일예로， 본 발명에서 티-캐드헤린 유전자 중의 서열번호 l(rs3865188)로 표시되는 서열의 27번째 염기의 유전자형이 ΊΤ 이고 아디포넥틴 유전자 중의 서열번호 2(rs2241767)의 27번째 염기의 유전자형이 M인 경우， 또는 상기 서열번호 1의 27번째 염기의 유전자형이 TT이고 서열번호 2의 27번째 염기의 유전자형이 GA, M인 경우 대장암 발병 위험도가 높다고 예측될 수 있다. In another embodiment, the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the T-cadherin gene is ΊΤ and the genotype of the 27th base of SEQ ID NO: 2 (rs2241767) in the adiponectin gene is M. In this case, or when the genotype of the 27th base of SEQ ID NO: 1 is TT and the genotype of the 27th base of SEQ ID NO: 2 is GA or M, it may be predicted that the risk of colon cancer is high.
본 발명의 구체적인 실시예에서는， rs3865188: AA 와 rs2241767: GG 유전자형에 비해 rs3865188: TT 와 rs2241767: AA 유전자형을 가진 사람이 대장암에 대한 위험도에 대해 감수성이 2.485배 높은 것으로 확인되었다. 그리고 rs3865188: AA 와 rs2241767: GG유전자형에 비해 rs3865188: TT 와 rs2241767: GA, AA 유전자형을 가진 사람이 대장암에 대한 위험도에 대해
감수성이 2.3이배 높은 것을 확인할 수 있었다. In a specific embodiment of the present invention, it was confirmed that a person with rs3865188: TT and rs2241767: AA genotypes was 2.485 times more susceptible to colorectal cancer than the rs3865188: AA and rs2241767: GG genotypes. And rs3865188: AA and rs2241767: compared to GG genotypes rs3865188: TT and rs2241767: GA and AA genotypes were associated with risk for colon cancer. It was confirmed that the sensitivity is 2.3 times higher.
다른 일예로， 본 발명에서 티-캐드헤린 유전자 중의 서열번호 l(rs3865188)로 표시되는 서열의 27번째 염기의 유전자형이 π 이고 아디포넥틴 '유전자 중의 서열번호 3(rs2241767)의 27번째 염기의 유전자형이 CC인 경우 대장암 발병 위험도가 높다고 예측될 수 있다. In another embodiment, the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the T-cadherin gene is π and the genotype of the 27th base of SEQ ID NO: 3 (rs2241767) in the adiponectin gene is CC. Can be expected to be at high risk for colorectal cancer.
본 발명의 구체적인 실시예에서는， rs3865188 : M 와 rs3821799 : TT 유전자형에 비해 rs3865188 : Ή 와 rs3821799 : CC 유전자형을 가진 사람이 대장암에 대한 위험도에 대해 감수성이 3.573배 높은 것으로 확인되었다. 다른 일예로， 본 발명에서 티-캐드헤린 유전자 중의 서열번호 l(rs3865188)로 표시되는 서열의 27번째 염기의 유전자형이 π 이고 아디포넥된 유전자 중의 서열번호 4(rs3774261)의 27번째 염기의 유전자형이 GG인 경우 대장암 발병 위험도가 높다고 예측될 수 있다. In a specific embodiment of the present invention, it was confirmed that a person with rs3865188: Ή and rs3821799: CC genotypes was 3.573 times more susceptible to colorectal cancer than the rs3865188: M and rs3821799: TT genotypes. As another example, the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the T-cadherin gene in the present invention is π, and the 27th base of SEQ ID NO: 4 (rs3774261) in the adiponected gene. This GG can be expected to increase the risk of colon cancer.
본 발명의 구체적인 실시예에서는， rs3865188 : AA 와 rs3774261 : AA 유전자형에 비해 rs3865188 : TT .와 rs3774261 GG 유전자형을 가진 사람이 대장암에 대한 위험도에 대해 감수성이 4.257배 높은 것으로 확인되었다. 다른 일예로, 본 발명에서 티-캐드헤린 유전자 중의 서열번호 l(rs3865188)로 표시되는 서열의 27번째 염기의 유전자형이 π 이고 아디포넥틴 유전자 증의 서열번호 5(rs6773957)의 27번째 염기의 유전자형이 GG인 경우 대장암 발병 위험도가 높다고 예측될 수 있다. In a specific embodiment of the present invention, it was confirmed that a person with rs3865188: TT. And rs3774261 GG genotypes was 4.257 times more susceptible to risk of colorectal cancer than the rs3865188: AA and rs3774261: AA genotypes. In another embodiment, the genotype of the 27th base of the sequence represented by SEQ ID NO: l (rs3865188) in the T-cadherin gene is π, and the genotype of the 27th base of SEQ ID NO: 5 (rs6773957) of adiponectin genesis is GG. Can be expected to be at high risk for colorectal cancer.
본 발명의 구체적인 실시예에서는， rs3865188 : AA 와 rs6773957 : AA 유전자형에 비해 rs3865188 : TT 와 rs6773957 : GG 유전자형을 가진 사람이 대장암에 대한 위험도에 대해 감수성이 3.992배 높은 것으로 확인되었다. 본 발명에서, 환자는 대장암 발병 전의 일반 환자로서 대장암 발병 위험도를 예측하여 관리하고자 하는 환자일 수 있다. 또는， 대장암이 이미 발병한 환자일 수 있다. In a specific embodiment of the present invention, it was confirmed that a person with rs3865188: TT and rs6773957: GG genotypes was 3.992 times more susceptible to colorectal cancer than rs3865188: AA and rs6773957: AA genotypes. In the present invention, the patient may be a general patient before the onset of colorectal cancer, and may be a patient to predict and manage the risk of colorectal cancer. Alternatively, the patient may have already developed colorectal cancer.
본 발명에서, 환자로부터 얻은 시료는 조직， 세포， 전혈， 혈청, 혈장， 타액， 객담， 뇌척수액ᅳ또는 뇨 등을 포함하며， 이들 시료로부터 유전자 시료를 얻는데, 그 유전자 시료는 DNA, mRNA , 또는 mRNA로부터 합성되는 cDNA를 포함한다. In the present invention, a sample obtained from a patient includes tissue, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid ᅳ or urine, etc., and obtain a genetic sample from these samples, the genetic sample is DNA, mRNA, or mRNA CDNA synthesized from.
본 발명에서 용어, "예측" 이란 환자에 대하여 대장암이 발병할
가능성이 있는지， 대장암이 발병할 가능성이 상대적으로 높은지， 또는 대장암이 이미 발병하였는지 여부를 판별하는 것을 말한다. 본 발명의 방법은 임의의 특정 환자에 대한 대장암 발병 위험도가 높은 환자로써 특별하고 적절한 관리를 통하여 발병 시기를 늦추거나 발병하지 않도록 하는 데 사용할 수 있다. 또한, 본 발명의 방법은 대장암을 조기에 진단하여 가장 적절한 치료 방식을 선택함으로써 치료 결정을 하기 위해 임상적으로 사용될 수 있다. In the present invention, the term "prediction" means that colorectal cancer will develop in a patient. This is to determine whether there is a possibility, whether the colorectal cancer is relatively high, or whether colorectal cancer has already occurred. The method of the present invention is a patient at high risk of developing colorectal cancer for any particular patient and can be used to prevent or delay the onset of the disease through special and appropriate management. In addition, the methods of the present invention can be used clinically to make treatment decisions by early diagnosis of colorectal cancer and selecting the most appropriate treatment regimen.
본 발명에서 용어， "다형성 (polymorphi sm) "이란 하나의 유전자 좌위 ( locus)에 두 가지 이상의 대립유전자 (al lele)가 존재하는 경우를 말하며 다형성 부위 중에서， 사람에 따라 단일 염기만이 다른 것을 단일 염기 다형성 (s ingl e nucleot ide polymorphi sm , SNP)이라 한다. 바람직한 다형성 마커는 선택된 집단에서 1% 이상， 더욱 바람직하게는 .10% 또는 20% 이상의 발생빈도를 나타내는 두 가지 이상의 대립유전자를 가진다. As used herein, the term "polymorphi sm" refers to a case in which two or more alleles exist in one locus. It is called s ingl e nucleotide polymorphism (SNP). Preferred polymorphic markers have two or more alleles which exhibit an incidence of at least 1%, more preferably at least .10% or at least 20% in the selected population.
본 발명에서 용어， "대립유전자 (al lele) "는 상동염색체의 동일한 유전자좌위에 존재하는 한 유전자의 여러 타입을 말한다. 대립유전자는 다형성을 나타내는데 사용되기도 하며, 예컨대， SNP은 두 종류의 대립인자 (bi al l el e)를 갖는다. As used herein, the term “al lele” refers to several types of genes that exist at the same locus of homologous chromosomes. Alleles are also used to indicate polymorphism, for example SNPs have two alleles (bi al el e).
또 하나의 양태로서， 본 발명은 환자에 있어서의 대장암 발병 위험도를 예측하기 위한 조성물을 제공한다. As another aspect, the present invention provides a composition for predicting the risk of developing colorectal cancer in a patient.
상기 조성물은 환자로부터 단리된 유전자 시료에 대하여， 티ᅳ캐드해린 유전자 중의 서열번호 UNCBI refSNP ID : rs3865188)로 표시되는 서열의 27번째 염기를 확인하기 위한 시약을 함유하는 것을 특징으로 한다. 일예로， 본 발명의 조성물에 함유되는 시약은， 바람직하게는 티ᅳ캐드헤린 유전자 중의 서열번호 KNCBI refSNP ID: rs3865188)로 표시되는 서열의 27번째 염기를 포함하는 10개 이상의 연속 염기로 구성되는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 포함한다 The composition is characterized by containing a reagent for identifying the 27th base of the sequence represented by SEQ ID NO: UNCBI refSNP ID: rs3865188) in the Tischadd Harin gene with respect to the genetic sample isolated from the patient. In one embodiment, the reagent contained in the composition of the present invention is preferably a poly consisting of 10 or more consecutive bases including the 27th base of the sequence represented by SEQ ID NO: KNCBI refSNP ID: rs3865188 in the Tibucatherin gene. Nucleotides or complementary polynucleotides thereof
또한, 상기 조성물은 환자로부터 단리된 유전자 시료에 대하여， 아디포넥틴 유전자 중의 서멸번호 2(NCBI refSNP ID: rs2241767)로 표시되는 서열의 27번째 염기， 아디포넥틴 유전자 중의 서열번호 30 BI refSNP ID : rs3821799)로 표시되는 서열의 27번째 염기， 아디포넥틴 유전자 중의
서열번호 4(NCBI refSNP ID : rs3774261)로 표시되는 서열의 27번째 염기， 및 아디포넥틴 유전자 중의 서열번호 5(NCB I refSNP ID : rs6773957)로 표시되는 서열의 27번째 염기로 이루어진 군에서 선택되는 하나 이상의 염기를 확인하기 위한 시약을 더욱 포함할 수 있다. In addition, the composition is represented by the 27th base of the sequence represented by the asterisk number 2 (NCBI refSNP ID: rs2241767) in the adiponectin gene, SEQ ID NO: 30 BI refSNP ID: rs3821799) in the adiponectin gene for the gene sample isolated from the patient Of the adiponectin gene, the 27th base of the sequence One selected from the group consisting of the 27th base of the sequence represented by SEQ ID NO: 4 (NCBI refSNP ID: rs3774261), and the 27th base of the sequence represented by SEQ ID NO: 5 ( NCB I re fSNP ID: rs6773957) in the adiponectin gene It may further include a reagent for identifying the above base.
일예로, 상기 조성물에 함유되는 시약은， 아디포넥틴 유전자 중의 서열번호 2(NCBI refSNP ID : rs2241767)로 표시되는 서열의 27번째 염기， 아디포넥틴 유전자 중의 서열번호 30 BI refSNP ID : rs3821799)로 표시되는 서열의 27번째 염기， 아디포넥틴 유전자 중의 서열번호 40 BI refSNP 10： rs3774261)로 표시되는 서열의 27번째 염기ᅳ 및 아디포넥틴 유전자 중의 서열번호 5(NCBI refSNP ID : rs6773957)로 표시되는 서열의 27번째 염기로 이루어진 군에서 선택되는 하나 이상의 염기를 포함하는 10개 이상의 연속 염기로 구성되는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 더욱 포함할 수 있다. In one embodiment, the reagent contained in the composition is the 27th base of the sequence represented by SEQ ID NO: 2 (NCBI refSNP ID: rs2241767) in the adiponectin gene, and the sequence represented by SEQ ID NO: 30 BI refSNP ID: rs3821799 in the adiponectin gene). 27th base, group consisting of the 27th base of the sequence represented by SEQ ID NO: 40 BI refSNP 10: rs3774261) in the adiponectin gene and the 27th base of the sequence represented by SEQ ID NO: 5 (NCBI refSNP ID: rs6773957) in the adiponectin gene It may further comprise a polynucleotide consisting of 10 or more consecutive bases comprising one or more bases selected from or complementary polynucleotides thereof.
따라서， 본 발명은 일 양태로서 상기 폴리뉴클레오티드를 제공한다. 본 발명에 따른 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드는 10개 이상， 바람직하게는 10 내지 100개， 보다 바람직하게는 20 내지 60개， 보다 더 바람직하게는 40 내지 60개의 연속 염기로 구성될 수 있다. Accordingly, the present invention provides the polynucleotide in one aspect. The polynucleotide according to the present invention or its complementary polynucleotide may be composed of 10 or more, preferably 10 to 100, more preferably 20 to 60, even more preferably 40 to 60 consecutive bases. have.
본 발명에 따른 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드는 다형성 서열 (polymorphi c sequence)이다. 다형성 서열 (polymorphi c sequenc)이란 뉴클레오티드 서열 중에 단일염기다형을 나타내는 다형성 부위 (polymorphi c si te)를 포함하는 서열을 말한다. 다형성 부위 (polymorphi c s i te)란 다형성 서열 중 단일염기다형이 일어나는 부위를 말한다. 본 발명에 있어서 상기 폴리뉴클레오티드는 DNA 또는 R A일 수 있다. Said polynucleotides or their complementary polynucleotides according to the invention are polymorphic c sequences. The polymorphic sequence (polymorphi c sequenc) refers to a sequence comprising a polymorphic site (polymorphi c si te) that represents a monobasic polymorphism in the nucleotide sequence. A polymorphic site (polymorphic c s i te) refers to a site where a monobasic polymorphism occurs in the polymorphic sequence. In the present invention, the polynucleotide may be DNA or R A.
다른 예로， 본 발명의 조성물에 함유되는 시약은， 바람직하게는 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드와 특이적으로 흔성화하는 폴리뉴클레오티드를 포함할 수 있다. As another example, the reagent contained in the composition of the present invention may preferably include a polynucleotide which specifically hybridizes with the polynucleotide or its complementary polynucleotide.
따라서 본 발명은 상기 폴리뉴클레오티드 또는 그의 상보적 플리뉴클레오티드와 특이적으로 흔성화하는 폴리뉴클레오티드를 일
양태로서 제공한다. Accordingly, the present invention relates to a polynucleotide that specifically hybridizes with the polynucleotide or its complementary polynucleotide. It provides as an aspect.
본 발명에 있어서, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드와 특이적으로 흔성화하는 폴리뉴클레오티드는 대립형질 특이적 (al lele-speci f ic) 폴리뉴클레오티드이다. In the present invention, the polynucleotide that specifically hybridizes with the polynucleotide or its complementary polynucleotide is an all lele-speci fic polynucleotide.
대립형질 특이적 폴리뉴클레오티드는 각 대립형질에 특이적으로 흔성화하는 것을 의미한다. 즉， 다형성 서열 중에 존재하는 다형성 부위의 염기를 특이적으로 구별할 수 있도록 흔성화하는 것을 말한다. 여기에서, 흔성화란 보통 엄격한 조건， 예를 들어 1M 이하의 염 농도 및 25 이상의 온도 하에서 보통 수행될 수 있다. Allele specific polynucleotide means to specifically hybridize to each allele. In other words, it refers to the hybridization so that the bases of the polymorphic sites present in the polymorphic sequence can be specifically distinguished. Here, localization can usually be carried out under stringent conditions, for example salt concentrations below 1 M and temperatures above 25.
본 발명에 있어서， 상기 대립형질 특이적 폴리뉴클레오티드는 대립 유전자 특이적 프로브일 수 있다. 즉， 본 발명에 있어서, 프로브는 흔성화 프로브를 의미하는 것으로， 핵산의 상보성 가닥에 서열 특이적으로 결합할 수 있는 을리고뉴클레오티드를 의마한다. 본 발명의 .대립형질 특이적 프로브는 같은 종의 두 개체로부터 유래한 핵산 단편 중에서 다형성 부위가 존재하여， 한 개체로부터 유래한 DNA단편에는 흔성화 하나， 다른 개체로부터 유래한 단편에는 흔성화하지 않는다. 이 경우 흔성화 조건은 대립형질간의 흔성화 강도에 있어서 유의한 차이를 보여 대립형질 중 하나에만 흔성화되도록 충분히 엄격해야 한다. 이러한 본 발명의 프로브는 중앙 부위가 다형성 서열의 다형성 부위와 정렬하는 것이 바람직하다. 이에 따라 서로 다른 대립형질성 형태 간에 좋은 흔성화 차이를 유발할 수 있다. 본 발명의 프로브는 대립형질을 검출하여 대장암 위험도를 예측하기 위한 마이크로어레이 등의 진단 키트나 예측 방법 둥에 사용될 수 있다. In the present invention, the allele specific polynucleotide may be an allele specific probe. In other words, in the present invention, the probe means a hybridization probe, and refers to a ligonucleotide capable of sequence-specific binding to the complementary strand of a nucleic acid. Of the present invention . Allele-specific probes have polymorphic sites in nucleic acid fragments derived from two individuals of the same species, which are common to DNA fragments derived from one individual but not to fragments derived from other individuals. In this case, the conditions for homogenization should be strict enough to only localize to one of the alleles, showing a significant difference in the intensities of alleles. In the probe of the present invention, the central region is preferably aligned with the polymorphic region of the polymorphic sequence. This can lead to good localization differences between different allelic forms. The probe of the present invention can be used in diagnostic kits or prediction methods such as microarrays for detecting alleles and predicting the risk of colorectal cancer.
또한 본 발명에 있어서， 상기 대립형질 특이적 폴리뉴클레오티드는 대립 유전자 특이적 프라이머일 수 있다. 프라이머의 적절한 길이는 사용 목적에 따라 달라질 수 있으나， 일반적으로 15 내지 30개의 염기로 구성된다. 프라이머 서열은 주형과 완전하게 상보적일 필요는 없으나， 주형과 흔성화할 정도로 충분히 상보적이어야 한다. 상기 프라이머는 다형성 부위를 포함하는 DNA 서열에 흔성화하여 다형성 부위를 포함하는 DNA 단편을 증폭시킨다. 본 발명의 프라이머는 대립형질을 검출하여 대장암 위험도를 예측하기 위한 마이크로어레이 등의 진단 키트나 예측 방법 등에 사용될 수 있다.
다른 예로， 본 발명의 조성물에 함유되는 시약은， 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드에 의해 코딩되는 폴리펩티드를 포함할 수 있다. In addition, in the present invention, the allele specific polynucleotide may be an allele specific primer. Appropriate length of the primer may vary depending on the intended use, but generally consists of 15 to 30 bases. The primer sequence need not be completely complementary to the template but must be sufficiently complementary to hybridize with the template. The primer amplifies a DNA fragment comprising the polymorphic site by generalizing to a DNA sequence comprising the polymorphic site. The primer of the present invention can be used in diagnostic kits or prediction methods such as microarrays for detecting alleles and predicting the risk of colon cancer. In another embodiment, the reagent contained in the composition of the present invention may include a polypeptide encoded by the polynucleotide or its complementary polynucleotide.
따라서 본 발명은 상기 폴리뉴클레오티드를 코딩하는 폴리펩티드를 일 양태로서 제공한다. Thus, the present invention provides, as an aspect, a polypeptide encoding the polynucleotide.
이러한 폴리펩티드는 대장암 위험도 예측용 조성물， 마이크로어레이 또는 키트 등에서 사용될 수 있다. 다르게는 상기 폴리펩티드를 대신하여 상기 폴리펩티드에 대한 항체를 사용할 수 있다. Such polypeptides may be used in compositions, microarrays or kits for predicting colorectal cancer risk. Alternatively, antibodies to the polypeptide can be used in place of the polypeptide.
본 발명에서 항체란, 당해 분야에서 공지된 용어로서 항원성 부위에 대해서 지시되는 특이적인 단백질 분자를 의미한다. 본 발명의 목적상， 항체는 본 발명의 SNP 마커를 포함하는 폴리펩티드에 대해 특이적으로 결합하는 항체를 의미한다. 이러한 항체는 각 유전자를 통상적인 방법에 따라 발현백터에 클로닝하여 상기 마커 유전자에 의해 코딩되는 단백질을 얻고， 얻어진 단백질로부터 통상적인 방법에 의해 제조될 수 있다. 여기에는 상가단백질에서 만들어질 수 있는 부분 펩티드도 포함되며, 본 발명의 부분 펩티드로는, 최소한 7개 아미노산， 바람직하게는 9개 아미노산， 더욱 바람직하게는 12개 이상의 아미노산을 포함한다. 본 발명의 항체의 형태는 특별히 제한되지 않으며 폴리클로날 항체， 모노클로날 항체 또는 항원 결합성을 갖는 것이면 그것의 일부도 본 발명의 항체에 포함되고 모든 면역 글로불린 항체가 포함된다. 나아가， 본 발명의 항체에는 인간화 항체 등와 특수 항체도. 포함된다. 본 발명의 대장암 발병 위험도 예측용 마커의 검출에 사용되는 항체는 2개의 전체 길이의 경쇄 및 2개의 전체 길이의 중쇄를 가지는 완전한 형태뿐만 아니라 항체 분자의 기능적인 단편올 포함한다. 항체 분자의 기능적인 단편이란 적어도 항원 결합 기능을 보유하고 있는 단편을 뜻하며 Fab , F(ab ' ) , F(ab ' ) 2 및 Fv등이 있다. In the present invention, an antibody means a specific protein molecule directed to an antigenic site as a term known in the art. For the purposes of the present invention, antibody means an antibody that specifically binds to a polypeptide comprising the SNP marker of the present invention. Such an antibody is cloned into an expression vector according to a conventional method to obtain a protein encoded by the marker gene, and can be prepared by a conventional method from the obtained protein. It also includes partial peptides that can be made from an elevated protein, and the partial peptide of the present invention includes at least 7 amino acids, preferably 9 amino acids, more preferably 12 or more amino acids. The form of the antibody of the present invention is not particularly limited and a part thereof is included in the antibody of the present invention and all immunoglobulin antibodies are included as long as they are polyclonal antibody, monoclonal antibody or antigen-binding agent. Furthermore, the antibodies of the present invention also include humanized antibodies and special antibodies. Included. Antibodies used in the detection of markers for predicting the risk of colorectal cancer onset of the present invention include functional fragments of antibody molecules as well as complete forms having two full length light chains and two full length heavy chains. The functional fragment of an antibody molecule means the fragment which has at least antigen binding function, and includes Fab, F (ab '), F (ab') 2, and Fv.
본 발명의 조성물에 포함되는 상기의 폴리뉴클레오티드， 이와 특이적으로 흔성화하는 폴리뉴클레오티드， 또는 그에 의해 특이적으로 코딩되는 폴리펩티드 또는 그의 cDNA는 또한， 대장암 위험도 예측용 마이크로어레이 또는 키트의 제조를 위한 용도로써 제공된다. 상기 마이크로어레이 또는 키트는 당업자에게 공지된 통상적인 방법에 의해
제작돨수 있다. The polynucleotide of the present invention, the polynucleotide specifically hybridizing thereto, or the polypeptide specifically encoded by the polynucleotide thereof or the cDNA thereof may also be used for the preparation of a microarray or kit for predicting colorectal cancer risk. It is provided for use. The microarray or kit may be prepared by conventional methods known to those skilled in the art. Can be manufactured.
본 발명에서 상기 마이크로어레이는 본 발명의 폴리뉴클레오티드， 폴리펩티드, cDNA 등을 포함하는 것을 제외하고는 통상적인 마이크로어레이로. 이루어질 수 있다. 마이크로어레이 상에서의 핵산의 흔성화 및 흔성화 결과의 검출은 당업계에 잘 알려져 있다, 상기 검출은 예를 들면, 핵산 시료를 형광 물질， 예를 들면， Cy3 및 Cy5와 같은 물질을 포함하는 검출가능한 신호를 발생시킬 수 있는 표지 물질로 표지한 다음， 마이크로어레이 상에 흔성화하고 상기 표지 물질로부터 발생하는 신호를 검출함으로써 흔성화 결과를 검출할 수 있다. In the present invention, the microarray is a conventional microarray except that the polynucleotide, polypeptide, cDNA and the like of the present invention. Can be done. Detection of nucleic acid on the microarray and the results of the localization are well known in the art, wherein the detection is for example detectable nucleic acid samples comprising fluorescent materials, for example, substances such as Cy3 and Cy5. The labeling result can be detected by labeling with a labeling substance capable of generating a signal, then by waving on a microarray and detecting a signal generated from the labeling substance.
본 발명에서 상기 키트는 본 발명의 폴리뉴클레오티드, 폴리펩티드， cDNA등 뿐만 아니라 분석 방법에 적합한 한 종류 또는 그 이상의 다른 구성 성분 조성물， 용액 또는 장치가 포함될 수 있다. 일 양태로서， 본 발명의 키트는 PCR을 수행하기 위해 필요한 필수 요소를 포함하는 키트일 수 있으며， 테스트 튜브 또는 다른 적절한 컨테이너， 반웅 완층액 (pH 및 마그네슘 농도는 다양)， 데옥시뉴클레오티드 (dNTPs), Taq—폴리머라아제 및 역전사효소와 같은 효소， DNase, RNAse 억제제， DEPCᅳ수 (DEPC-water) 및 멸균수 등을 추가로 포함할 수 있다. 다른 일 양태로서， 본 발명의 키트는 DNA칩을 수행하기 위해 필요한 필수 요소를 포함하는 대장암 위험도 예측용 키트일 수 있으며， DNA 칩 카트는 상기 SNP 에 대한 특이적인 폴리뉴클레오티드， 프라이머 또는 프로브가 부착되어 있는 기판을 포함하고 기판은 정량 대조구 유전자 또는 그의 단편에 해당하는 핵산을 포함할 수 있다. In the present invention, the kit may include not only polynucleotides, polypeptides, cDNAs, etc. of the present invention but also one or more other component compositions, solutions, or devices suitable for analytical methods. In one aspect, the kit of the present invention may be a kit containing the necessary elements necessary to perform PCR, test tubes or other suitable containers, semiperiods (pH and magnesium concentrations vary), deoxynucleotides (dNTPs) Enzymes such as Taq-polymerase and reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, and sterile water. In another aspect, the kit of the present invention may be a kit for predicting colorectal cancer risk including essential elements necessary for performing a DNA chip, and the DNA chip cart is attached to a polynucleotide, primer or probe specific for the SNP. The substrate may comprise a nucleic acid corresponding to the quantitative control gene or fragment thereof.
본 발명의 SNP 의 유전자형의 확인은 시퀀싱 분석， 자동염기서열분석기를 사용한 시퀀싱 분석， 파이로시퀀싱 (pyroseQuencing), 마이크로어레이에 의한 흔성화， PCR-RELP법 (restriction fragment length polymorphism) , PCRᅳ SSCP법 (single strand conformation polymorphism) , PCR-SS0법 (specific sequence oligonucleotide), PCR-SS0법과 도트 하이브리드화법을 조합한 AS0 (allele specific oligonucleotide) 하이브리드화법， TaqMan-PCR법， MALDI— T0F/MS법， RCA법 (rolling circle amplification), HRM (high resolution melting)법， 프라이머 신장법， 서던
블롯 하이브리드화법， 도트 하이브리드화법 등의 공지의 방법에 의하여 수행될 수 있다. Identification of the genotype of the SNP of the present invention, sequencing analysis, sequencing analysis using an automatic base sequence analyzer, pyrose sequencing, microarray shake, PCR-RELP method (restriction fragment length polymorphism), PCR ᅳ SSCP method single strand conformation polymorphism (PCR), PCR-SS0 method (specific sequence oligonucleotide), PCR-SS0 method and dot hybridization method combined AS0 (allele specific oligonucleotide) hybridization method, TaqMan-PCR method, MALDI—T0F / MS method, RCA method (rolling circle amplification), HRM (high resolution melting) method, primer extension method, Southern It can be performed by a well-known method, such as a blot hybridization method and a dot hybridization method.
나아가，상기 SNP다형성의 결과들은 당업계에서 일반적으로 사용되는 통계학적 분석 방법을 이용하여 통계처리 할 수 있으며， 예를 들면， 스튜던트 t-검정 (Student 's t-test), 카이-스퀘어 테스트 (Chi-square test )， 선형 회귀선 분석 (linear regression line analysis) , 다변량 로지스틱 ᅵ회귀분석 (multiple logistic regression analysis) 등을 통해 얻은 연속 .변수 (continuous variables) , 절대 변수 (categorical variables) , 대응비 (odds ratio) 및 95%신뢰구간 (confidence interval) 등의 변수를 이용하여 분석할 수 있다. In addition, the results of the SNP polymorphism can be statistically processed using statistical analysis methods commonly used in the art, for example, Student's t-test, chi-square test ( consecutive, such as obtained by the Chi-square test), a linear regression analysis (linear regression line analysis), multivariate logistic regression analysis (multiple logistic regression analysis). Analysis can be performed using variables such as continuous variables, categorical variables, odds ratio, and 95% confidence interval.
【발명의 실시를 위한 형태】 [Form for implementation of invention]
이하， 본 발명을 실시예에 의해 상세히 설명한다. 단， 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명이 하기 실시예에 의해 한정되는 것은 아니다. 실시예 1. 통계학적 분석의 개요 Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, the present invention is not limited by the following examples. Example 1.Summary of Statistical Analysis
본 발명에서는 통계학적인 분석을 통해 티 -캐드헤린의 rs3865188과 아디포넥틴의 rs2241767, rs3821799, rs3774261, rs6773957과의 각각 . In the present invention, through the statistical analysis of T-cadherin rs3865188 and adiponectin rs2241767, rs3821799, rs3774261, rs6773957, respectively.
상호작용에 의한 .대장암 위험도를 제시하였다. 또한 이들 상호작용 The risk of colon cancer by interaction was suggested. Also these interactions
SNP-SNP의 복합 유전자형과 혈액 내 아디포넥틴 양과의 연관성을 Association between SNP-SNP Complex Genotype and Adiponectin Level in Blood
발견하였다. Found.
본 발명에서는 시료 수집은 연세대학교지선하 연구팀의 대사성 증후군 코호트 내 대장암 시료를 사용하였고， 아디포넥틴 혈액 내 수치는 메스디아 아디포넥틴 ELISA kit를 활용하였다. 본 발명을 위해 다음과 같은 통계분석 도구를 활용하였다. 정규성 검정에 따라 T-test와 AN0VA를 사용하였고， 그 외 비모수 검정을 통해 통계 분석 하였다. 유전자-유전자 상호작용은 기본적으로 로지스틱 회귀 분석을 통해 분석하였고， 나이와 체질량 계수에 대하여 보정하였다.
실시예 2. SNP-SNP상호작용을 분석하기 위한 집단구성 본 발명을 위해 연세대학교 보건대학원 지선하 연구팀에서 대사성 증후군 코호트 연구에서 사용한 집단에서 대장암 환자 325명과 정상군 In the present invention, sample collection was performed using a colorectal cancer sample in the metabolic syndrome cohort of the Yonsei University Underground Research Team, and the adiponectin blood level was used for the media adiponectin ELISA kit. The following statistical analysis tool was used for the present invention. T-test and AN0VA were used according to the normality test, and other nonparametric tests were used for statistical analysis. Gene-gene interactions were basically analyzed by logistic regression and corrected for age and body mass coefficients. Example 2 Population Configuration for Analyzing SNP-SNP Interaction For the present invention, 325 patients with colorectal cancer and a normal group in the group used in the metabolic syndrome cohort study by the Underground Research Team at Yonsei University Health School
977명을 선별하였다. 임상학적 특성에서 두 집단의 차이가 명료하게 977 people were selected. The difference between the two groups in clinical characteristics is clearly
나누어진다 (표 2). Divided (Table 2).
【표 2】 Table 2
아디포넥틴 유전자 SNP는 rsl82052, rs 17366568, rs2241767, rs3821799, rs3774261, rs6773957로， 연세대 지선하 교수팀에 의해 기 보고된 한국인 코호트의 genotype data를 바탕으로 Haploview v4.2를 이용하여 연관불균형 관계를 분석하였다. 6개 SNP중 rs2241767, rs3821799, rs3774261, rs6773957는 강한 연관불균형 관계로 블록 (linkage diseui 1 ibr ium block, LD block)을 형성하는 것으로 확인되었다. (도 1， =98 및 /=99) 실시예 4. 대장암과 티-케드해린 SNP (rs3865188) 및 아디포넥틴 유전자 SNP와의 연관성 분석
대장암 환자를 대상으로 rs3865188, rsl82052, rs 17366568, rs2241767, rs3821799, rs3774261, rs6773957들의 유전자형에 따른 유의성을 검정하였다. 그 결과 티ᅳ케드헤린의 rs3865188만이 유전자형에 따른 대장암 환자와 정상군 간의 차이를 보여 주었고 (p=0.0474)， 아디포넥틴 SNP는 대장암과의 연관성을 보이지 않았다 (표 3). The adiponectin gene SNPs were rsl82052, rs 17366568, rs2241767, rs3821799, rs3774261, and rs6773957. The association disparity was analyzed using Haploview v4.2 based on the genotype data of the Korean cohort reported by Yonsei University. Of the six SNPs, rs2241767, rs3821799, rs3774261, and rs6773957 were found to form a linkage diseui 1 ibrium block (LD block) due to strong linkage disequilibrium. (FIG. 1, = 98 and / = 99) Example 4. Analysis of association between colorectal cancer and T-Kedharin SNP (rs3865188) and adiponectin gene SNP The genotypes of rs3865188, rsl82052, rs 17366568, rs2241767, rs3821799, rs3774261, and rs6773957 were tested in colorectal cancer patients. As a result, only rs3865188 of T. ketherin showed the difference between colon cancer patients and normal group according to genotype (p = 0.0474), and adiponectin SNP was not associated with colorectal cancer (Table 3).
【표 3] [Table 3]
티 -캐드헤린의 rs3865188에 대하여 위험도 (odds rat io)를 로지스틱 회귀 분석을 활용하여 실시하였다. 위험도는 T-dominance 모드와 T-recess ive 모드로 나누어 분석 하였다. T-dominance 모드는 TT유전자형과 TA 유전자형을 하나의 군으로 보고 M 유전자형에 대하여 위험도를 분석한 것으로 분석 결과는 유의하지 않았다. T— recessive 모드는 TA유전자형과 M 유전자형을 하나의 군으로 보고 TT 유전자형에 대하여 위험도를 측정한 것으로 Π 유전자형이 ΤΑ유전자형과 유전자형 군보다 1.577배 위험도가 높은 것을 확인 할 수 있었다 (/>=() .0144) (표 4) . 따라서， 한국인에서 티 -캐드헤린의 rs3865188의 유전자형으로 대장암 위험도를 예측 할 수 있음을 확인하였다. The risk (odds rat io) for T-cadherin rs3865188 was performed using logistic regression analysis. Risk was divided into T-dominance mode and T-recess ive mode. In the T-dominance mode, the TT genotype and the TA genotype were considered as one group and the risk analysis was performed for the M genotype. The T- recessive mode measured the TA genotype and M genotype as one group and measured the risk for the TT genotype. It was confirmed that the Π genotype was 1.577 times higher than the ΤΑ genotype and genotype group (/> = (). .0144) (Table 4). Therefore, it was confirmed that T-cadherin rs3865188 genotype can predict colon cancer risk in Korean.
【표 4】 Table 4
Point 95% wald Point 95% wald
Effects Pᅳ value est imate Confidence l imits Effects P ᅳ value est imate Confidence l imits
T-dominance 1.090 0.848 1.402 0.5003 T-dominance 1.090 0.848 1.402 0.5003
T-recess ive 1.577 1.095 2.272 0.0144T-recess ive 1.577 1.095 2.272 0.0144
Tᅳ Dominance ； TT+TA vs . AA T ᅳ Dominance; TT + TA vs. AA
T-recessive ； TT vs . TA+AA , T-recessive; TT vs. TA + AA,
Adjusted for age and BMI . 실시예 6. rs3865188과 rs2241767 간의 상호작용에 의한 대장암 위험도 예측 Adjusted for age and BMI. Example 6 Prediction of Colorectal Cancer Risk by Interaction Between rs3865188 and rs2241767
본 발명에서 티 캐드헤린의 rs3865188 SNP와 달리， 아디포넥틴 SNP는 대장암과의 연관성이 발견되지 않았다. 이에， 본 발명에서는 티 캐드헤린의 rs3865188 SNP 과 아디포넥틴 SNP 간의 유전자-유전자 상호작용을 이용한 분석을 실시하였다. Unlike the rs3865188 SNP of tcadherin in the present invention, adiponectin SNP was not found to be associated with colorectal cancer. Thus, in the present invention, the gene-genetic interaction between rs3865188 SNP and adiponectin SNP of T-cadherin was analyzed.
rs3865188과 아디포넥틴의 4개 SNP에 대한 유전자—유전자 상호작용에 의한 대장암 위험도를 로지스틱 회귀분석을 통해 측정하였다. 그 중 아디포넥틴의 rs2241767와 rs3865188와의 조합이 rs3865188 단일 SNP에 의한 대장암 위험도보다 훨씬 높은 것을 확인 할 수 있었다. rs3865188 : M 와 rs2241767 : GG유전자형에 비해 rs3865188 : TT와 rs2241767 : AA유전자형을
가진 사람이 대장암에 대한 위험도에 대해 감수성이 2.485배 높았다. 그리고 rs3865188: AA 와 rs2241767: ' GG 유전자형에 비해 rs3865188: TT 와 r 82241767： GA, M 유전자형을 가진 사람이 대장암에 대한 위험도에 대해 감수성이 2.301배 높은 것으로 확인하였다 (표 5). The risk of colorectal cancer due to gene-gene interactions for the four SNPs of rs3865188 and adiponectin was measured by logistic regression analysis. Among them, the combination of adiponectin rs2241767 and rs3865188 was much higher than the risk of colorectal cancer caused by rs3865188 single SNP. rs3865188: M and rs2241767: GG genotype rs3865188: TT and rs2241767: AA genotype Those who had a susceptibility to colorectal cancer were 2.485 times higher. And rs3865188: AA and rs2241767: 'compared to the GG genotype rs3865188: TT and r 82241767: It was confirmed that people with GA, M genotype is 2.301 times more susceptible to risk of colorectal cancer (Table 5).
【표 5] [Table 5]
아디포넥틴의 LD block의 두 번째 SNP인 rs3821799은 rs3865188과와 조합도 위험도를 확인 할 수 있었다. rs3865188: AA 와 rs3821799: TT 유전자형에 비해 rs3865188: TT 와 rs3821799: CC 유전자형을 가진 사람이
대장암에 대한 위험도에 대해 감수성이 3.573배 높은 것으로 확인되었다 (표 6) . The second SNP of rs3821799 in the LD block of adiponectin was also confirmed to be in combination with rs3865188. rs3865188: AA and rs3821799: compared to TT genotype rs3865188: TT and rs3821799: a person with CC genotype The sensitivity to colorectal cancer was found to be 3.573 times higher (Table 6).
【표 6】 Table 6
아디포넥틴의 LD block의 세 번째 SNP인 rs3774261은 rs3865188과의 조합에서 6개의 SNP 중에서 가장 강력한 위험도를 확인 할 수 있었다. rs3865188 : AA 와 rs3774261 : AA 유전자형에 비해 rs3865188 : TT 와 rs3774261 GG 유전자형을 가진 사람이 대장암에 대한 위험도에 대해 감수성이 4.257배 높다 (표 7) .
【표 7] Rs3774261, the third SNP of the adiponectin LD block, was identified as the strongest of the six SNPs in combination with rs3865188. The rs3865188: TT and rs3774261 GG genotypes are 4.257 times more susceptible to colorectal cancer compared to the rs3865188: AA and rs3774261: AA genotypes (Table 7). [Table 7]
아디포넥틴의 LD block의 마지막 SNP인 rs6773957은 rs3865288과의 조합에서 위험도를 확인 할 수. 있었다. rs3865188: AA 와 rs6773957: AA 유전자형에 비해 rs3865188: TT 와 rs6773957: GG 유전자형을 가진 사람이 대장암에 대한 위험도에 대해 감수성이 3.992배 높다 (표 8). Rs6773957, the last SNP of the adiponectin LD block, can be identified in combination with rs3865288. there was. rs3865188: AA and rs6773957: Compared to AA genotypes rs3865188: TT and rs6773957: Persons with GG genotype are 3.992 times more susceptible to risk for colorectal cancer (Table 8).
【표 8】
0.803 1.556 0.907 0.907 Table 8 0.803 1.556 0.907 0.907
(0.467- 1. (0.713-3. (0.582- 1. (0.582- 1. (0.467-1. (0.713-3. (0.582-1. (0.582-1.
AA 1 AA 1
382) 393) 415) 415) 382) 393) 415) 415)
0.4281 0.2666 0.6672 0.6672 o 1.003 1.224 1.210 1.106 1.1060.4281 0.2666 0.6672 0.6672 o 1.003 1.224 1.210 1.106 1.106
(0.6O2 L5- 1. (0.610-2. (0.728- 1. (0.728- i .(0.6O2 L5- 1. (0.610-2. (0.728-1.
AG AG
608) 1 962) 373) 680) 680) i 608) 1 962) 373) 680) 680) i
0.9917 0.4009 0.5799 0.6368 0.6368 o 0.9917 0.4009 0.5799 0.6368 0.6368 o
1.249 1 l.270 3.992 1.266 1.2661.249 1 l .270 3.992 1.266 1.266
O O
(0.657-2. (0.632-2. (1.487-1 (0.734-2. (0.734-2. rs67739 GG 1 (0.657-2. (0.632-2. (1.487-1 (0.734-2. (0.734-2.rs67739 GG 1)
375) 552) 0.716) 183) 183) 57 375) 552) 0.716) 183) 183) 57
0.4951 0.5019 0.0060 0.3966 0.3966 0.4951 0.5019 0.0060 0.3966 0.3966
1.002 1.028 1.324 1.014 1.0141.002 1.028 1.324 1.014 1.014
ΑΑ,Α (0.667-1. (0.752-2. (0.684- 1. (0.684- 1. ΑΑ, Α (0.667-1. (0.752-2. (0.684-1. (0.684-1.
G 532) 583) 331) 503) 503) G 532) 583) 331) 503) 503)
0.9931 0.9013 0.3315 0.9439 0.9439 0.9931 0.9013 0.3315 0.9439 0.9439
1.130 1.130
1.047 1.236 1.645 1.130 1.047 1.236 1.645 1.130
(0.751 - 1. (0.751-1.
AG,G (0.666- 1. (0.788-1. (0.908-2. AG, G (0.666-1. (0.788-1. (0.908-2.
702) 702)
G 644) 939) 977) 702) G 644) 939) 977) 702)
0.5568 0.8427 0.3568 0.1004 0.5568 0.5568 0.8427 0.3568 0.1004 0.5568
실시예 10. rs3865188과 rs3774261 간의 상호 작용과 인체 혈액 내 아디포넥틴양 Example 10 Interaction between rs3865188 and rs3774261 and the amount of adiponectin in human blood
본 발명에서는 유전자-유전자 상호작용을 이용하여 대장암의 위험도를 예측 할 수 있었다. 특히, 본 발명자들이 발견한 rs3865188는 단독적으로 위험도를 예측 할 수 있지만 rs3865188과 아디포넥틴의 LD block이 형성되는 4개의 SNP와의 조합을 통해 보다 세분화되었고 고위험군 예측을 할 수 있었다. In the present invention, it was possible to predict the risk of colorectal cancer using gene-gene interactions. In particular, the rs3865188 found by the present inventors can predict the risk alone, but the combination of rs3865188 and four SNPs in which the LD block of adiponectin is formed can be further refined and predict the high risk group.
기존에 보고된 대장암과 아디포넥틴의 혈액 내 수치와 상관성을 이용하여 본 발명에서 rs3865188과 아디포네틱 4개 SNP의 상호작용에 의한 아디포넥틴 혈액 내 수치 분석한 결과， 가장 위험도가 높았던 rs3865188과
rs3774261 조합에서 가장 위험도가 높았던 조합인 rs3865188: TT 와 rs3774261: GG와 아디포넥틴의 혈액 내 수치가 rs3865188: AA와 rs3774261: AA 유전자형에 비해 현저히 낮은 것을 확인 할 수 있었다 (도 2; rs3865188:AA 와 rs3774261: M의 아디포넥틴 중앙값 수치 7.835 ug/ml , rs3865188: TT 와 rs3774261: GG의 아디포넥틴 중앙값 수치 4.800 ug/ml ， P=0.0017). 본 발명에서는 질환관련 유전자-유전자 상호작용과 실질적인 임상변수와의 관계를 확인 할 수 있었다.
As a result of analyzing the adiponectin blood level by the interaction of rs3865188 and adiponetic four SNPs in the present invention using the previously reported correlation with color values of colorectal cancer and adiponectin, rs3865188 and The most dangerous combinations of rs3774261, rs3865188: TT and rs3774261: GG and adiponectin, were found to be significantly lower than those of the rs3865188: AA and rs3774261: AA genotypes (Figure 2; rs3865188: AA and rs3774261: Median adiponectin value of M, 7.835 ug / ml, rs3865188: TT and rs3774261: median adiponectin value of GG, 4.800 ug / ml, P = 0.0017). In the present invention, the relationship between disease-related gene-gene interactions and substantial clinical variables could be identified.
Claims
【청구항 1】 【Claim 1】
환자로부터 얻은 유전자 시료에 대하여， Regarding genetic samples obtained from patients,
티-캐드헤린 (T-cadher in) 유전자 중의 서열번호 KNCBI refSNP ID : rs3865188)로 표시되는 서열의 27번째 염기의 다형성을 확인하는 단계를 포함하는， Comprising the step of confirming the polymorphism of the 27th base of the sequence represented by sequence number KNCBI refSNP ID: rs3865188) in the T-cadherin gene,
대장암 발병 위험도를 예측하기 위한 정보를 제공하는 방법. A method of providing information to predict the risk of developing colon cancer.
【청구항 2】 【Claim 2】
제 1항에 있어서， 상기 서열번호 1의 27번째 염기의 유전자형이 ΊΤ 인 경우가 M또는 AT 인 경우보다 대장암 발병 위험도가 높다고 예측하는 것을 특징으로 하는 방법 . The method according to claim 1, wherein the genotype of the 27th base of SEQ ID NO: 1 is ΊΤ, and the risk of colon cancer is predicted to be higher than that of M or AT.
[청구항 3】 [Claim 3]
제 1항에 있어서， In clause 1,
환자로부터 얻은 유전자 시료에 대하여， Regarding genetic samples obtained from patients,
아디포넥틴 (adiponect in) 유전자 중의 서열번호 2(NCBI refSNP ID: rs2241767)로 표시되는 서열의 27번째 염기의 다형성， 아디포넥틴 유전자 중의 서열번호 3(NCBI refSNP ID : rs3821799)로 표시되는 서열의 27번째 염기의 다형성， 아디포넥틴 유전자 중의 서열번호 4(NCBI refSNP ID : Polymorphism of the 27th base of the sequence represented by SEQ ID No. 2 (NCBI refSNP ID: rs2241767) in the adiponectin gene, and the 27th base of the sequence represented by SEQ ID No. 3 (NCBI refSNP ID: rs3821799) in the adiponectin gene. Polymorphism, SEQ ID NO: 4 in the adiponectin gene (NCBI refSNP ID:
rs3774261)로 표시되는 서열의 27번째 염기의 다형성, 및 아디포넥틴 유전자 중의 서열번호 5(NCBI refSNP ID : rs6773957)로 표시되는 서열의 27번째 염기의 다형성으로 이루어진 군에서 선택되는 하나 이상의 다형성을 확인하는 단계를 더욱 포함하는 방법 . Confirming one or more polymorphisms selected from the group consisting of a polymorphism at the 27th base of the sequence represented by (rs3774261) and a polymorphism of the 27th base of the sequence represented by SEQ ID No. 5 (NCBI refSNP ID: rs6773957) in the adiponectin gene. How to further include .
【청구항 4】 【Claim 4 】
제 3항에 있어서， 상기 서열번호 1의 27번째 염기의 유전자형이 π 이고 서열번호 2의 27번째 염기의 유전자형이 Μ인 경우， 또는 상기 서열번호 1의 27번째 염기의 유전자형이 ΊΤ 이고 서열번호 2의 27번째 염기의 유전자형이 GA , Μ인 경우 대장암 발병 위험도가 높다고 예측하는
것을 특징으로 하는 방법 The method of claim 3, wherein the genotype of the 27th base of SEQ ID NO: 1 is π and the genotype of the 27th base of SEQ ID NO: 2 is Μ, or the genotype of the 27th base of SEQ ID NO: 1 is ΊΤ and SEQ ID NO: 2 If the genotype of the 27th base is GA or Μ, the risk of developing colon cancer is predicted to be high. Method characterized by
【청구항 5] [Claim 5]
제 3항에 있어서, 상기 서열번호 1의 27번째 염기의 유전자형이 TT 이고 서열번호 3의 27번째 염기의 유전자형이 CC인 경우 대장암 발병 위험도가 높다고 예측하는 것을 특징으로 하는 방법. The method of claim 3, wherein when the genotype of the 27th base of SEQ ID NO: 1 is TT and the genotype of the 27th base of SEQ ID NO: 3 is CC, the risk of developing colon cancer is predicted to be high.
【청구항 6】 【Claim 6】
계 3항에 있어서， 상기 서열번호 1의 27번째 염기의 유전자형이 TT 이고 서열번호 4의 27번째 염기의 유전자형이 GG인 경우 대장암 발병 위험도가 높다고 예측하는 것을 특징으로 하는 방법. The method according to item 3, wherein when the genotype of the 27th base of SEQ ID NO: 1 is TT and the genotype of the 27th base of SEQ ID NO: 4 is GG, the risk of developing colon cancer is predicted to be high.
【청구항 7】 【Claim 7】
제 3항에 있어서， 상기 서열번호 1의 27번째 염기의 유전자형이 π 이고 서열번호 5의 27번째 염기의 유전자형이 GG인 경우 대장암 발병 위험도가 높다고 예측하는 것을 특징으로 하는 방법. The method according to claim 3, wherein when the genotype of the 27th base of SEQ ID NO: 1 is π and the genotype of the 27th base of SEQ ID NO: 5 is GG, the risk of developing colon cancer is predicted to be high.
【청구항 8】 【Claim 8】
티-캐드헤린 유전자 중의 서열번호 1(NCBI refSNP ID : rs3865188)로 표시되는 서열의 27번째 염기를 포함하는 10개 이상의 연속 염기로 With 10 or more consecutive bases including the 27th base of the sequence represented by SEQ ID No. 1 (NCBI refSNP ID: rs3865188) in the T-cadherin gene
구성되는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 The polynucleotide or its complementary polynucleotide
포함하는， Including，
대장암 발병 위험도 예측용 조성물. Composition for predicting the risk of developing colon cancer.
【청구항 9】 【Claim 9】
거 18항에 있어서， 아디포넥틴 유전자 중의 서열번호 2(NCBI refSNP ID : rs2241767)로 표시되는 서열의 27번째 염기, 아디포넥틴 유전자 중의 서열번호 3(NCBI refSNP ID : rs3821799)로 표시되는 서열의 27번째 염기, 아디포넥틴 유전자 중의 서열번호 4(NCBI refSNP ID : rs3774261)로 표시되는 서열의 27번째 염기， 및 아디포넥틴 유전자 중의 서열번호 5(NCBI refSNP ID :
rs6773957)로 표시되는 서열의 27번째 염기로 이루어진 군에서 선택되는 하나 이상의 염기를 포함하는 10개 이상의 연속 염기로 구성되는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 더욱 포함하는 조성물. According to item 18, the 27th base of the sequence represented by SEQ ID No. 2 (NCBI refSNP ID: rs2241767) in the adiponectin gene, the 27th base of the sequence represented by SEQ ID No. 3 (NCBI refSNP ID: rs3821799) in the adiponectin gene, The 27th base of the sequence represented by SEQ ID NO: 4 in the adiponectin gene (NCBI refSNP ID: rs3774261), and SEQ ID NO: 5 in the adiponectin gene (NCBI refSNP ID: A composition further comprising a polynucleotide consisting of 10 or more consecutive bases including one or more bases selected from the group consisting of the 27th base of the sequence represented by (rs6773957) or a complementary polynucleotide thereof.
[청구항 10】 [Claim 10]
제 8항 또는 게 9항의 폴리뉴클레오티드와 특이적으로 흔성화하는 폴리뉴클레오티드를 포함하는, Containing a polynucleotide that is specifically common with the polynucleotide of item 8 or item 9,
대장암 발병 위험도 예측용 조성물. Composition for predicting the risk of developing colon cancer.
【청구항 11】 【Claim 11】
제 10항에 있어서， 상기 특이적으로 흔성화하는 폴리뉴클레오티드가 프로브 또는 프라이머인 조성물. The composition according to claim 10, wherein the specifically common polynucleotide is a probe or primer.
【청구항 12】 【Claim 12】
게 8항 또는 게 9항의 폴리뉴클레오티드에 의해 코딩되는 플리펩티. 또는 이에 특이적인 항체를 포함하는, A flipepti encoded by a polynucleotide of crab 8 or crab 9. or containing antibodies specific thereto,
대장암 발병 위험도 예측용 조성물. Composition for predicting the risk of developing colon cancer.
【청구항 13】 【Claim 13】
제 8항 또는 제 9항의 폴리뉴클레오티드， 이와 흔성화하는 The polynucleotide of claim 8 or 9, common therewith
폴리뉴클레오티드， 이에 의해 특이적으로 코딩되는 폴리펩티드， 이에 특이적인 항체， 또는 상기 폴리펩티드의 cDNA를 포함하는ᅳ A polynucleotide, a polypeptide specifically encoded thereby, an antibody specific for the same, or cDNA of the polypeptide.
대장암 발병 위험도 예측용 마이크로어레이 . Microarray for predicting risk of colon cancer.
. .
【청구항 14] [Claim 14]
게 8항 또는 제 9항의 폴리뉴클레오티드， 이와 흔성화하는 The polynucleotide of item 8 or item 9, common therewith
폴리뉴클레오티드， 이에 의해 특이적으로 코딩되는 폴리펩티드， 이에 특이적인 항체， 또는 상기 폴리펩티드의 cDNA를 포함하는， A polynucleotide, a polypeptide specifically encoded thereby, an antibody specific for the same, or cDNA of the polypeptide,
대장암 발병 위험도 예측용 키트.
A kit for predicting the risk of developing colon cancer.
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