KR101187317B1 - Polymorphic markers predicting susceptibility to diffuse-type gastric cancer and the prediction method thereof using the same - Google Patents

Abstract

The invention polymorphism in sporadic gastric sensitivity predicted polymorphic marker, haplotype marker and this scattered gastric sensitivity related to a prediction method, and more particularly disseminated gastric cancer and RPS6KB2, PTPRCAP, CORO1B and GPR152 gene having a relationship with for And a method for predicting and analyzing the risk of diffuse gastric cancer by identifying haplotypes.

RPS6KB2, PTPRCAP, CD45-AP, CORO1B, GPR152, Monobasic Polymorphism (SNP), Haplotype, Gastric Cancer, Susceptibility, Genetic Association

Description

Polymorphic markers predicting susceptibility to diffuse-type gastric cancer and the prediction method about using the same}

The present invention relates to a polymorphic marker for disseminated gastric cancer susceptibility, haplotype marker, and a method for predicting disseminated gastric cancer susceptibility using the same.

Gastric cancer is caused by a combination of genetic and environmental factors. Infection, smoking, drinking and unhealthy eating habits of Helicobacter pylori are known risk factors that increase the risk of gastric cancer (Correa P, Cancer). Res . 52: 6735-6740, 1992; Peek RM et al ., Nat Rev Cancer. 2002, 2, 28-37; Tsugane S et al ., Br J Cancer. 90: 128-134, 2004; Palli D, J Gastroenterol . 35: 84-89, 2000). Genetic mutations of the IL1B, IL1R2, IL10, TLR4, TNF, and PSCA genes have been reported to be significantly associated with gastric cancer susceptibility (El-Omar EM et. al ., Nature . 404: 398-402, 2000; El-Omar EM, Gut . 48: 743-747, 2001; Hold GL et al ., Gastroenterol ogy . 132: 905-912, 2007; Sakamoto H et al ., Nat Genet . 40: 730-740, 2008). In particular, IL1B, IL1R2, IL10, TLR4, and TNF are cellular signals that activate the immune response, and the sequential changes found before the onset of intestinal-type, ie inflammatory reactions, chronic gastritis and gastric acid deficiency progression. It is known to promote. PSCA, on the other hand, is a diffuse-type gastric cancer gene discovered through a genome-wide association study that may affect the division and proliferation of epithelial cells. However, the genes identified so far cannot explain all of the sensitivity of gastric cancer, and there are more gastric cancer genes that are not yet known.

Phosphorylation and dephosphorylation of tyrosine residues regulated by protein tyrosine kinase and protein tyrosine phosphatase maintain a dynamic balance and serve as a switch for cellular signaling. Hunter T & Cooper JA, Annu Rev Biochem . 54: 897-930, 1985). Phosphorylation and dephosphorylation of tyrosine regulate cell division, adhesion and migration, and imbalance of phosphorylation and dephosphorylation is known to be associated with cancer development (Ostman A et al ., Nat Rev Cancer . 6: 307-320, 2006).

Src family kinase (SFK) is a cancer gene that promotes cell division, migration, invasion and angiogenesis, inhibits death and induces angiogenesis around cancer cells (Summy JM & Gallick GE, Cancer Metastasis Rev. 22: 337-358. 2003). If tyrosine residues located at the carboxyl terminus of the SFK protein are phosphorylated, SFK loses its activity. Protein tyrosine phosphatase C (PTPRC), better known as CD45, is known to activate SFK by eliminating tyrosine phosphate groups that inhibit SFK activity (Mustelin T et al ., Proc Natl Acad Sci USA. 86: 6302-6306, 1989; Mustelin T et al ., Eur J Immunol. 22: 1173-1178, 1992; Trowbridge IS & Thomas ML, Annu Rev Immunol . 12: 85-116, 1994). In this process, PTPRCAP (CD45-AP) binds to PTPRC to help the action of PTPRC and to enhance SFK activity (Matsuda A et. al ., J Exp Med . 187: 1863-1870, 1998; Takeda A et al ., J Biol Chem . 269: 2357-2360, 1994; Takeda A et al ., Blood . 103: 3340-3447, 2004).

Abnormally activated SFK interferes with the placement of E-cadherin protein in the cell membrane, disrupting cell-to-cell binding (Owen DW et al ., Mol Biol Cell . 11: 51-64, 2000; Irby RB & Yeatman TJ. Cancer Res . 62: 2669-2674, 2002; Avizienyte E et al ., Nat Cell Biol . 4: 632-638, 2002), altering the properties of cells so that they can penetrate surrounding tissues (Behrens J et. al ., J Cell Biol . 120: 757-766, 1993). In fact, overexpression or activation of SFK has been observed in many epithelial cell carcinomas (Summy JM & Gallick GE, 2003). In particular, it is noteworthy that E-cadherin, a representative gene for diffuse gastric cancer, is regulated by SFK (Boussioutas A et. al ., Cancer Res . 63: 2569-2577, 2003; Guilford P, Nature . 392: 402-405, 1998). Thus, PTPRCAP is likely to bind to PTPRC to activate SFK and to help SFK transmit various signals related to cancer development to cells.

In this regard, the present inventors analyzed the association of the PTPRCAP gene with gastric cancer susceptibility through a patient-control study. The result is PTPRCAP Ten single nucleotide polymorphisms (SNPs) present in the gene and adjacent RPS6KB2 , CORO1B , and GPR152 genes were found to be significantly associated with susceptibility to diffuse gastric cancer, in particular, PTPRCAP The present invention was completed by confirming that the polymorphism located in the promoter can be used to predict the expression level of the gene and the genetic predisposition of diffuse gastric cancer.

An object of the present invention is to provide a kit for predicting the scattered stomach cancer susceptibility using the monobasic polymorphism marker for predicting the scattered gastric cancer.

Another object of the present invention is to provide a microarray for dispersing gastric cancer susceptibility prediction integrated with the monobasic polymorphism marker for dispersing gastric cancer susceptibility.

Another object of the present invention is to provide a haplotype marker for predicting diffuse gastric cancer susceptibility in the human genome 11q13 region.

Another object of the present invention is to provide a method for predicting disseminated gastric cancer susceptibility using the monobasic polymorphism marker for predicting disseminated gastric cancer.

In order to achieve the above object, the present invention provides a kit for predicting the disseminated gastric cancer susceptibility comprising a probe or primer pair capable of detecting the scattered gastric cancer-related monobasic polymorphism marker present in the human genome 11q13 region.

The present invention also provides a microarray for predicting scattered gastric cancer susceptibility in which scattered gastric cancer-related monobasic polymorphism markers present in the human genome 11q13 region are integrated.

In addition, the present invention provides a polymorphic site of 1 rs1476792 (SEQ ID NO: 82), which is a single nucleotide polymorphism marker in the human genome 11q13 region, wherein the +112 th base is C; ② the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is T; (3) the + 301th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is A; ④ the +401 th base which is the polymorphic site of rs1790752 (SEQ ID NO: 85) is T; The polymorphic site of rs13859 (SEQ ID NO: 86) is the +401 base; ⑥ the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), is T; ⑦ the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is A; ⑧ the +301 th base which is the polymorphic site of rs2302264 (SEQ ID NO: 89) is A; The polymorphic site of rs1808279 (SEQ ID NO: 90) at the +220 th base is G; And a haploid marker for predicting diffuse gastric cancer susceptibility, wherein the +218 th base, which is the polymorphic site of rs1790761 (SEQ ID NO: 91), is G.

In addition, the present invention provides a polymorphic site of rs1476792 (SEQ ID NO: 82), which is a monobasic polymorphism marker in the human genome 11q13 region, wherein the +112 th base is T; ② the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is C; ③ The + 301th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is G; ④ the +401 th base which is the polymorphic site of rs1790752 (SEQ ID NO: 85) is C; The polymorphic site of rs13859 (SEQ ID NO: 86) is the +401 base; ⑥ the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), is G; ⑦ the + 101th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is G; ⑧ the +301 th base which is the polymorphic site of rs2302264 (SEQ ID NO: 89) is G; The +220 th base, the polymorphic site of rs1808279 (SEQ ID NO: 90), is A; And a haplotype marker for predicting diffuse gastric cancer susceptibility in which the + 218th base, which is the polymorphic site of rs1790761 (SEQ ID NO: 91), is A.

In addition, the present invention provides a method for detecting the scattered gastric cancer-related single nucleotide polymorphism marker for predicting diffuse gastric cancer.

Hereinafter, the term used by this invention is demonstrated.

Single Nucleotide Polymorphism (SNP) is the most frequent polymorph present in the human genome at a rate of about 0.1% (about 1 base to about 1000 bases). In other words, this monobasic polymorphism means a state in which a polymorphism is an AT base pair in the polymorphism, for example, when one base of the genomic gene is replaced with another base. In addition, there exist cases where each allele of the double-stranded chromosome is polymorphic (homogenous conjugation polymorphism) and when one side is wild type and the other is polymorphic (heterozygotic polymorphism). Such a single base variation may cause synthesis (nonsense variation) of incomplete protein due to codon mutation (synthesis of missed amino acid) or termination codon. Therefore, it is clear that the presence or absence of monobasic polymorphism is related to various diseases (eg SNP of p53 gene for lung cancer: Biros et. al ., Neoplasma 48 (5): 407-11, 2001) The importance of accurately determining the presence or absence of monobasic polymorphisms (SNP typing) is strongly recognized for purposes of diagnosis and genetic therapy. In addition, this monobasic polymorphism is also a useful polymorphic marker when searching for genes related to disease-prone properties or drug reactivity, and attracts attention as important genetic information for tailor-made medicine.

Haplotypes are a combination of single-base polymorphisms found in a population based on statistical probability, and are known to provide more accurate and reliable functional genetic information than each single base polymorphism.

11q13 refers to the thirteenth band of the long arm (q) below the centromere of chromosome 11.

Hereinafter, the present invention will be described in detail.

The present invention provides a kit for predicting disseminated gastric cancer susceptibility comprising a pair of primers capable of amplifying interstitial gastric cancer-related monobasic polymorphism markers present in the human genome 11q13 region.

Protein tyrosine phosphatase C (PTPRC), better known as CD45, is known to activate SFK by removing tyrosine phosphate groups that inhibit the activity of the cancer gene Src family kinase (SFK). At this time, PTPRCAP (CD45-AP) is combined with PTPRC serves to increase the activity of SFK. Abnormally activated SFK regulates the e-cadherin protein, a representative gene for diffuse-type gastric cancer, to interfere with the cell membrane.

In this regard, the inventors have selected 23 single nucleotide polymorphisms (SNPs) from 430 kb of the 11q13 region of the human genome where PTPRCAP is present and analyzed the association with gastric cancer through a patient-control study. . As a result, 10 monobasic polymorphisms in the 26 kb region consisting of RPS6KB2 , PTPRCAP , CORO1B and GPR152 genes were significantly associated with scattered gastric cancer susceptibility [rs1476792 (+ 112T>C; SEQ ID NO: 82), rs4930427 ( + 401C>T; SEQ ID NO: 83), rs1790753 (+ 301G>A; SEQ ID NO: 84), rs1790752 (+ 401C>T; SEQ ID NO: 85), rs13859 (+ 401C>T; SEQ ID NO: 86), rs869736 (+ 417G >T; SEQ ID NO: 87), rs872375 (+ 101G>A; SEQ ID NO: 88), rs2302264 (+ 301G>A; SEQ ID NO: 89), rs1808279 (+ 220A>G; SEQ ID NO: 90), rs1790761 (+ 218A> G SEQ ID NO: 91) (see FIG. 1). In addition, the minor alleles of each polymorphism were found to increase the susceptibility of scattered gastric cancer by more than 40% compared to the major alleles (see Table 2). Ten polymorphisms were strongly related to each other (R ² = 0.97), haplotype and diplotype The analysis also showed a significant correlation with gastric cancer (see Table 3). However, no significant association with intestinal-type was found (see Table 4).

In particular, PTPRCAP The rs869736 (-309G> T) polymorphism, located at the promoter, was not only significantly associated with susceptibility to diffuse gastric cancer (see Table 4), but also confirmed that it had a function of regulating promoter activity (see FIGS. 2 and 3). ). In other words, analysis of gastric cancer cell line (MKN28) using luciferase assay and EMSA (eletrophoretic mobility shift assay) technique revealed that the T allele of rs869736 polymorphism had a higher promoter activity and DNA-protein binding capacity than the G allele. It appeared to be stronger. In addition, in the in vivo mRNA expression test using the B cell line, the T allele was significantly associated with the increased expression level of PTPRCAP (see FIG. 4).

Thus, the monobasic polymorphism and haplotype of the present invention can be usefully used for predicting susceptibility of scattered gastric cancer.

Specifically, the present invention provides a kit for predicting diffuse gastric cancer susceptibility comprising a probe or primer pair capable of detecting any one or more scattered gastric cancer-related polymorphic sites selected from the following groups:

1) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the +112 th base, which is the polymorphic site of rs1476792 (SEQ ID NO: 82), is T or C, and includes the +112 th base Polynucleotides;

2) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is C or T and comprises the +401 th base Polynucleotides;

3) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the +301 th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is G or A and comprises the +301 th base Polynucleotides;

4) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +401 th base, which is the polymorphic site of rs1790752 (SEQ ID NO: 85), is C or T, and the +401 th base Polynucleotides;

5) Scattered gastric cancer-related association of the polymorphic site of rs13859 (SEQ ID NO: 86), where the +401 th base is C or T and 20 to 100 consecutive nucleic acid molecules comprising the +401 th base or complementary nucleic acid molecules Polynucleotides;

6) Scattered gastric cancer-related association of the polymorphic site of rs869736 (SEQ ID NO: 87) with the +417 th base G or T and 20 to 100 consecutive nucleic acid molecules comprising the +417 th base or complementary nucleic acid molecules Polynucleotides;

7) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is G or A; Polynucleotides;

8) Scattered gastric cancer-related association of the polymorphic site of rs2302264 (SEQ ID NO: 89), wherein the +301 th base is G or A and 20 to 100 consecutive nucleic acid molecules comprising the +301 th base or complementary nucleic acid molecules Polynucleotides;

9) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +220 th base, which is the polymorphic site of rs1808279 (SEQ ID NO: 90), are A or G, and the +220 th base Polynucleotides; And

10) Scattered gastric cancer-related association of the polymorphic site of rs1790761 (SEQ ID NO: 91) with the A + G base of 20 or 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +218 base Polynucleotide.

The probe of the kit is preferably designed to specifically bind to the polynucleotide under stringent hybridization conditions, and 15 to 15 selected in the polynucleotide to include 15 to 50 consecutive bases comprising the polymorphic site. Any complementary to oligonucleotides of 50mer length, preferably 15-30mer length, more preferably 18-25mer length can be used.

The specific binding means that non-specific hybrids are not formed, but specific hybrids are formed, and the strict hybridization conditions can be determined based on the melting temperature (Tm) of the nucleic acid forming the hybrids according to a conventional method. have. As a washing condition that can maintain a specific hybridization state, it is usually a condition of about 1 × SSC, 0.1% SDS, 37 ° C., more strictly, a condition of about 0.5 × SSC, 0.1% SDS, 42 ° C., and more stringent. For example, "0.1 x SSC, 0.1% SDS, 65" can be mentioned.

The probe can also be used by immobilization on any solid substrate. The solid substrate also includes a gene tip, cDNA micro array, oligo DNA array, membrane filter (membrane filter).

The primer pair of the kit is preferably selected from the group consisting of the following primer pairs 1 to 10, but is not limited thereto, 15 to 50 mer long, preferably 15 to 30 mer long, more preferably 18 Both forward and reverse primer pairs of length from 25 to 25 mer can be used.

Alternatively, the primer pair may consist of 15 to 50 consecutive bases including the polymorphic site, and may have at least one oligonucleotide having the base of the polymorphic site at the 3 ′ end. By having a polymorphic site at the 3 'end, it is apparent to those skilled in the art that the amplification reaction does not occur in a genomic DNA sample obtained from an individual in which the polymorphic site is not mutated by mutation of the single nucleic acid molecule.

Primer pair 1: forward primer set forth in SEQ ID NO: 22 and reverse primer set forth in SEQ ID NO: 23;

Primer pair 2: forward primer set forth in SEQ ID NO: 29 and reverse primer set forth in SEQ ID NO: 28;

Primer pair 3: forward primer set forth in SEQ ID NO: 32 and reverse primer set forth in SEQ ID NO: 33;

Primer pair 4: forward primer set forth in SEQ ID NO: 35 and reverse primer set forth in SEQ ID NO: 36;

Primer pair 5: forward primer set forth in SEQ ID NO: 38 and reverse primer set forth in SEQ ID NO: 39;

Primer pair 6: forward primer set forth in SEQ ID NO: 44 and reverse primer set forth in SEQ ID NO: 452;

Primer pair 7: forward primer set forth in SEQ ID NO: 47 and reverse primer set forth in SEQ ID NO: 48;

Primer pair 8: forward primer set forth in SEQ ID NO: 50 and reverse primer set forth in SEQ ID NO: 51;

Primer pair 9: forward primer set forth in SEQ ID NO: 53 and reverse primer set forth in SEQ ID NO: 54; And

Primer pair 10: The forward primer set forth in SEQ ID NO: 56 and the reverse primer set forth in SEQ ID NO: 57.

In this case, the kit may further include a deoxynucleotide mixture (dNTP mixture) and a buffer as a component of the PCR reaction, and may further include a thermostable DNA polymerase such as Taq DNA polymerase. In addition, the kit of the present invention may further include a fluorescent material such as 6-FAM, NED or HEX, agarose and electrophoresis buffer solution required to confirm the PCR results. In addition, the kit of the present invention may be provided in the form of a premix of the amplification reaction element with the primer pair.

The present invention also provides a microarray for dispersing gastric cancer susceptibility prediction in which any one or more oligonucleotides are selected from the following groups:

1) Scattered gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +112 th base, which is the polymorphic site of rs1476792 (SEQ ID NO: 82);

2) scattered gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83);

3) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +301 th base, the polymorphic site of rs1790753 (SEQ ID NO: 84);

4) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +401 th base, the polymorphic site of rs1790752 (SEQ ID NO: 85);

5) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +401 th base, the polymorphic site of rs13859 (SEQ ID NO: 86);

6) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +417 th base, the polymorphic site of rs869736 (SEQ ID NO: 87);

7) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88);

8) scattered gastric cancer-related oligonucleotides consisting of 5 to 25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +301 th base, the polymorphic site of rs2302264 (SEQ ID NO: 89);

9) Scattered gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +220 th base, which is the polymorphic site of rs1808279 (SEQ ID NO: 90); And

10) Scattered gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +218 th base, which is the polymorphic site of rs1790761 (SEQ ID NO: 91).

The oligonucleotide is not hybridized when there is a mismatch with an amplified product labeled with a fluorescent material while amplifying the DNA contained in the sample, and when the match is hybridized, the fluorescence is detected. It can be predicted. At this time, it is apparent to those skilled in the art that hybridization is not performed even by mismatch of a single nucleic acid molecule on the oligonucleotide.

The microarray of the present invention can be produced by methods known to those skilled in the art. The method of manufacturing the microarray is as follows. In order to immobilize the oligonucleotide as a probe DNA molecule on a microarray substrate, a micropipetting method using a piezoelectric method or a method using a pin-shaped spotter, etc. It is preferable to use but is not limited thereto. The substrate of the microarray is preferably coated with one active group selected from the group consisting of amino-silane, poly-L-lysine, and aldehyde. It is not. In addition, the substrate may be selected from the group consisting of slide glass, plastic, metal, silicon, nylon membrane, and nitrocellulose membrane, but is not limited thereto.

In addition, the present invention provides a polymorphic site of 1 rs1476792 (SEQ ID NO: 82), which is a single nucleotide polymorphism marker in the human genome 11q13 region, wherein the +112 th base is C; ② the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is T; ③ The + 301th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is A; ④ the +401 th base which is the polymorphic site of rs1790752 (SEQ ID NO: 85) is T; The polymorphic site of rs13859 (SEQ ID NO: 86) is the +401 base; ⑥ the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), is T; ⑦ the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is A; ⑧ the +301 th base which is the polymorphic site of rs2302264 (SEQ ID NO: 89) is A; The polymorphic site of rs1808279 (SEQ ID NO: 90) at the +220 th base is G; And a haploid marker for predicting diffuse gastric cancer susceptibility, wherein the +218 th base, which is the polymorphic site of rs1790761 (SEQ ID NO: 91), is G.

In addition, the present invention provides a polymorphic site of rs1476792 (SEQ ID NO: 82), which is a monobasic polymorphism marker in the human genome 11q13 region, wherein the +112 th base is T; ② the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is C; ③ The + 301th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is G; ④ the +401 th base which is the polymorphic site of rs1790752 (SEQ ID NO: 85) is C; The polymorphic site of rs13859 (SEQ ID NO: 86) is the +401 base; ⑥ the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), is G; ⑦ the + 101th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is G; ⑧ the +301 th base which is the polymorphic site of rs2302264 (SEQ ID NO: 89) is G; The +220 th base, the polymorphic site of rs1808279 (SEQ ID NO: 90), is A; And a haplotype marker for predicting diffuse gastric cancer susceptibility in which the + 218th base, which is the polymorphic site of rs1790761 (SEQ ID NO: 91), is A.

In addition, the present invention is a scattered stomach cancer invention is a genomic DNA isolated from blood samples of individuals (experimental group) and control group

1) detecting the following scattered gastric cancer-related polymorphic sites in the DNA; And

3) A method of detecting the interstitial gastric cancer-related monobasic polymorphism marker of claim 1, comprising predicting the interstitial gastric cancer, comprising comparing the detection result of step 2) with a control group:

① Scattered gastric cancer-related poly of the polymorphic site of rs1476792 (SEQ ID NO: 82), wherein the +112 th base is T or C, and 20 to 100 consecutive nucleic acid molecules comprising the +112 th base or nucleic acid molecules complementary thereto Nucleotides;

(2) Scattered gastric cancer-related polys composed of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules thereof, wherein the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is C or T and comprises the +401 th base; Nucleotides;

③ The sporadic gastric cancer-related poly of the polymorphic site of rs1790753 (SEQ ID NO: 84), wherein the +301 th base is G or A, and is composed of 20 to 100 consecutive nucleic acid molecules including the +301 th base or nucleic acid molecules complementary thereto. Nucleotides;

(4) Scattered gastric cancer-related polys composed of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules thereof, wherein the +401 th base, which is the polymorphic site of rs1790752 (SEQ ID NO: 85), is C or T and comprises the +401 th base; Nucleotides;

Scattered gastric cancer-related poly, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules containing the +401 th base, which is the polymorphic site of rs13859 (SEQ ID NO: 86), is C or T, and the +401 th base Nucleotides;

(6) Scattered gastric cancer-related polys composed of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), is G or T and comprises the +417 th base; Nucleotides;

⑦ interstitial gastric cancer-related poly, consisting of 20-100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is G or A, and the +101 th base Nucleotides;

⑧ Scattered gastric cancer-related poly consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +301 th base, which is the polymorphic site of rs2302264 (SEQ ID NO: 89), is G or A, and the +301 th base Nucleotides;

⑨ The scattered gastric cancer-related poly of the polymorphic site of rs1808279 (SEQ ID NO: 90) is A or G, and is composed of 20 to 100 consecutive nucleic acid molecules including the + 220th base or nucleic acid molecules complementary thereto. Nucleotides; And

산 A sporadic gastric cancer-related poly consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the polymorphic site of rs1790761 (SEQ ID NO: 91) is A or G and the +218 base is included Nucleotides.

The detection method of step 1) includes sequencing analysis, hybridization by microarray, allele specific PCR, dynamic allele-specific hybridization (DASH), PCR extension analysis, restriction Restriction fragment length polymorphisms (RFLP), MALDI-TOF mass spectrometry or TaqMan techniques can be performed.

PCR detection and quantitation using double labeled fluorogenic oligonucleotide probes, commonly referred to as the "TaqMan ™" probes, can also be performed in accordance with the present invention. Such probes consist of short (eg, 20-25 bases) oligodeoxynucleotides labeled with two different fluorescent dyes. There is a reporter dye at the 5 'end of each probe and a quenching dye at the 3' end. Oligonucleotide probe sequences are complementary to internal target sequences present in PCR amplicons. If the probe is not damaged, energy transfer occurs between the two fluorophores and the emission from the reporter is quenched by FRET. During the elongation phase of PCR, the probe is cleaved by the 5 'nuclease activity of the polymerase used in the reaction so that the reporter is released from the oligonucleotide-quencher and an increase in reporter release intensity occurs. Thus, TaqMan ™ probes are oligonucleotides with labels and quencher, where the labels are released by the exonuclease action of the polymerase used in the amplification during amplification. This provides a real time measurement of amplification during synthesis. A variety of TaqMan ™ reagents are commercially available from Applied Biosystems (USA) as well as from various specialist vendors such as Biosearch Technologies (eg black hole quencher probes). Further details regarding double-labeled probe strategies are described in WO92 / 02638.

RPS6KB2 , PTPRCAP , CORO1B and GPR152 as above Since rs1476792, rs4930427, rs1790753, rs1790752, rs13859, rs869736, rs872375, rs2302264, rs1808279 and rs1790761 polymorphic markers and haplotype markers of genes are closely related to scattered gastric cancer susceptibility, it is possible to measure the susceptibility of predisposed gastric cancer by measuring them. It can be useful to prevent this, and can be used to analyze the genetic predisposition of diffuse gastric cancer.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

< Example  1> Selection of test subject

The present invention used 430 gastric cancer patients and 406 normal genomic DNA. Blood and tissue samples from gastric cancer patients and normal people were collected at Seoul National University Hospital, Hanyang University Guri Hospital, Inje University Paik Hospital, Chungnam National University Hospital, and Eulji University Hospital with the approval of the internal ethics committee of each institution. The control group included only those who were found to be normal by a medical examination, including gastroscopy or gastrointestinal angiography.

The age at diagnosis was 57.3 ± 12.9 years (mean ± standard deviation) and 52.1 ± 8.4 years in normal patients. The proportion of males was 66.5% in the patient group and 69.5% in the normal group, which was higher in both groups.

Gastric cancer patients were classified according to Lauren's classification. There were 178 enteric gastric cancer patients and 252 diffuse gastric cancer patients, and the mixed type was not included in the analysis. The stages of gastric cancer were composed of 42 patients in stage 1A, 66 patients in stage IB, 86 patients in stage II, 106 patients in stage IIIA, 58 patients in stage IIIB, and 72 patients in stage IV.

< Example  2> Analysis of Polymorphism

<2-1> DNA  extraction

Puregene ^™ in frozen gastric tissue or blood samples obtained from study subjects Genomic DNA was extracted using a DNA purification kit (Gentra, USA), or DNeasy ^® tissue kit (Qiagen, Germany). The extracted DNA was measured using PicoGreen ^® (Molecular Probes, Eugene, OR) fluorescent dye that specifically quantified only double-stranded DNA, and then the concentration was 2.5-10 ng / μl, which is suitable for genotyping. Stored.

<2-2> Selection of Regions for Polymorphism Analysis primer  design

Based on the International HapMap database (/www.hapmap.org/), 23 single nucleotide polymorphisms were selected from the 430 kb region of the 11q13 region of the human genome where PTPRCAP was present, and then the forward and reverse fryer for PCR for genotyping. Primer and extension reaction (Ext) primer sequences are provided in Table 1. Primers used for genotyping were designed using the Assay Design 3.1 (Sequenom, USA) program.

Primer Sequences for Monobasic Polymorphism Analysis SNP_ID Forward PCR Primer Reverse PCR primer Ext Primer rs2282502 ACGTTGGATGTGGTGACATCGAAGCAAAGC: SEQ ID NO: 1 ACGTTGGATGAGGGCAAGATGACTATGACC: SEQ ID NO: 2 CGGCCCCTGTTCTACCCTGA: SEQ ID NO: 3 rs10791899 ACGTTGGATGAGTGTCCAGTGGTCTGTAAC: SEQ ID NO: 4 ACGTTGGATGGGAAGGCTATCTGATCACTC: SEQ ID NO: 5 GAGTCAGTGACAGGGCTGG: SEQ ID NO: 6 rs3927807 ACGTTGGATGTCCAACCCATTTGTCCACTG: SEQ ID NO: 7 ACGTTGGATGTTACCTAGGTGTCCTCCTAG: SEQ ID NO: 8 TCCTAGGTCAGGATCCTGTT: SEQ ID NO: 9 rs1790740 ACGTTGGATGAGCTCCCAGGTAATACATGG: SEQ ID NO: 10 ACGTTGGATGTATATGAGTAGCCTCGCTCC: SEQ ID NO: 11 ACTTCCAAACAAGCTCTCAAG: SEQ ID NO: 12 rs7480390 ACGTTGGATGTGTTCACAACACCTTCCACC: SEQ ID NO: 13 ACGTTGGATGCGGAAGGACTGTGGAAGTTG: SEQ ID NO: 14 GTTGTTTTTCTCTTTCAAAAGCC: SEQ ID NO: 15 rs10896172 ACGTTGGATGTAGCCCAAACTCACACTGTG: SEQ ID NO: 16 ACGTTGGATGAAGATCCTAGGCAGAACTGC: SEQ ID NO: 17 TCTTCCCTAAGCCAGGAGC: SEQ ID NO: 18 rs1790733 ACGTTGGATGCTGCCCTTTCTGTAGAAGGG: SEQ ID NO: 19 ACGTTGGATGTTTCTGCCTGTGCTGCTGGAG: SEQ ID NO: 20 GTCCAGAGCCCGGGTGAGTGT: SEQ ID NO: 21 rs1476792 ACGTTGGATGACCCAGATCCTTCTCAGATC: SEQ ID NO: 22 ACGTTGGATGAGAATCGGGAGAAAAGGCTG: SEQ ID NO: 23 GGGTGAGGGTGGGATCAGA: SEQ ID NO: 24 rs917570 ACGTTGGATGAGTGAGTGAGGGTCGTGTTG: SEQ ID NO: 25 ACGTTGGATGTAATGAGGACAAGGCTCCAG: SEQ ID NO: 26 GACAAGGCTCCAGTGCTCCCCA: SEQ ID NO: 27 rs55987642 ACGTTGGATGTGCCCCTGATGATCTTATCC: SEQ ID NO: 28 ACGTTGGATGACAAGGCTCCTCTCACCTTC: SEQ ID NO: 29 CTTCCTCCTCCTCCAGC: SEQ ID NO: 30 rs4930427 ACGTTGGATGACAAGGCTCCTCTCACCTTC: SEQ ID NO: 29 ACGTTGGATGTGCCCCTGATGATCTTATCC: SEQ ID NO: 28 TTCCGGTTCTCTGCGGT: SEQ ID NO 31 rs1790753 ACGTTGGATGTCATTCCCAGAGGCAAACTG: SEQ ID NO: 32 ACGTTGGATGATTCTGCACGTGTTCCTGAG: SEQ ID NO: 33 CAAACTGCACAGGCCGGG: SEQ ID NO: 34 rs1790752 ACGTTGGATGTTGATGCTGTCCAGGACAGA: SEQ ID NO: 35 ACGTTGGATGATCGTGACTAAGGATGGCAG: SEQ ID NO: 36 GTCGCATGGCCCTGCCTCC: SEQ ID NO: 37 rs13859 ACGTTGGATGTTCTCCTTCCAGCCCAAGC: SEQ ID NO: 38 ACGTTGGATGTCCCTAACCCAGCCACACAC: SEQ ID NO: 39 CCTCAGTACCTGACGGGG: SEQ ID NO: 40 rs10274 ACGTTGGATGTGAAAGTGTGTGTCTGCTGG: SEQ ID NO: 41 ACGTTGGATGTTAATCTTCCACGGGAGCAG: SEQ ID NO: 42 GGGAGCAGTTGAGCGCGGGG: SEQ ID NO: 43 rs869736 ACGTTGGATGTTCTGCACATGTGTGACTCC: SEQ ID NO: 44 ACGTTGGATGTTCTAAAAGCCAGGCTGACC: SEQ ID NO: 45 GGAAACCTGGAGACAGA: SEQ ID NO: 46 rs872375 ACGTTGGATGTGCATCACCTCCTCCAGCTTC: SEQ ID NO: 47 ACGTTGGATGTTGGGAGGGCTATGGCTTAG: SEQ ID NO: 48 CTACCCCTGCTTCATGTCC: SEQ ID NO: 49 rs2302264 ACGTTGGATGATCCTCCACTTCCAGTCCTC: SEQ ID NO: 50 ACGTTGGATGTGAGAACTGTCACGAGGCAG: SEQ ID NO: 51 GTCTAGCCACCTTAGGGGT: SEQ ID NO: 52 rs1808279 ACGTTGGATGGGGAAATCGAGACCATCCT: SEQ ID NO: 53 ACGTTGGATGCAAGAAATTCACCCCAGTAGC: SEQ ID NO: 54 GTAGCTGGGACTACAGGCT: SEQ ID NO: 55 rs1790761 ACGTTGGATGCTGGGGCTCTGATCCAATAG: SEQ ID NO: 56 ACGTTGGATGGCCACTTGGCCTTTAGTTTG: SEQ ID NO: 57 TTTGGTGCCCTCCGTACCC: SEQ ID NO: 58 rs17501521 ACGTTGGATGTTTCTTCCTAGGTGCAGAGC: SEQ ID NO: 59 ACGTTGGATGTGAGGGCATAAGGTCTGAAG: SEQ ID NO: 60 GGCATAAGGTCTGAAGCCCAAG: SEQ ID NO: 61 rs4084113 ACGTTGGATGATCCGCAGGTGGACTGCTG: SEQ ID NO: 62 ACGTTGGATGAAAGGAGACCCAGGGTACTG: SEQ ID NO: 63 ACAGGTTTTCTTGTCTCTGTCC: SEQ ID NO: 64 rs2276120 ACGTTGGATGTGCGCAAAACTGTGATGCCC: SEQ ID NO: 65 ACGTTGGATGAAGGAAGGGGCAGACAGAGAC: SEQ ID NO: 66 CAGACAGAGACTAGAGGCG: SEQ ID NO: 67

<2-3> Genotyping

Genotypes of polymorphisms were determined by MassARRAY ^TM using MALDI-TOF mass spectrometry. The system (Sequenom, USA) was used.

Specifically, the first PCR reaction was the forward and reverse of 200 nM in 2.5 ng of genomic DNA, 1 × buffer, 1 mM MgCl ₂ , 200 μM dNTP mixture, 0.1 unit HotStart Taq polymerase (Solgent, Korea) mixture Primers were performed in 5 μl solutions, each added. The reaction conditions consisted of 45 cycles of 94 ° C., 20 seconds, 56 ° C., 30 seconds, and 72 ° C. for 1 minute after initial denaturation at 94 ° C. for 15 minutes, and a final extension step of 72 ° C. for 3 minutes. After the first PCR reaction, 0.3 units of SAP (shrimp alkaline phosphatase; Sequenom, USA) were added, and residual dNTP was removed by incubation at 37 ° C. for 20 minutes and 85 ° C. for 5 minutes. The second PCR reaction, hME extension, was performed by adding 50 μM d / ddNTP terminator mix, 600 nM Ext primer, and 0.576 unit thermo sequenase ™ enzyme (Sequenom, USA) to the reaction product. After the initial denaturation at 94 ° C. for 2 minutes, a short cycle of 94 ° C. 5 seconds, 52 ° C. 5 seconds, and 72 ° C. 5 seconds was repeated 40 times. After addition of 16 μl of distilled water and 3 mg of Clean Resin (Sequenom, USA), the final reaction product was transferred to SpectroChip (Sequenom, USA) and genotyped with an Analyzer Compact (Sequenom, USA) mass spectrometer.

<2-4> Statistical Analysis

A chi-square independent test was used to analyze the relationship between Hardy-Weinberg equilibrium (HWE) and gastric cancer susceptibility. No significant difference was found between the predicted and observed frequencies of genotypes in all 23 polymorphisms (HWE P> 0.05). Logistic regression was used to correct for gender and age differences between patient and control groups. All statistical analyzes were conducted using the SPSS 11.5 program.

As a result, as shown in FIG. 1, 10 monobasic polymorphisms in the 26 kb region consisting of RPS6KB2 , PTPRCAP , CORO1B, and GPR152 genes were significantly associated with scattered gastric cancer susceptibility [rs1476792 (+ 112T>C; sequence) No. 82), rs4930427 (+ 401C>T; SEQ ID NO: 83), rs1790753 (+ 301G>A; SEQ ID NO: 84), rs1790752 (+ 401C>T; SEQ ID NO: 85), rs13859 (+ 401C>T; SEQ ID NO: 86 ), rs869736 (+ 417G>T; SEQ ID NO: 87), rs872375 (+ 101G>A; SEQ ID NO: 88), rs2302264 (+ 301G>A; SEQ ID NO: 89), rs1808279 (+ 220A>G; SEQ ID NO: 90), rs1790761 (+ 218A>G; SEQ ID NO: 91)]. In addition, as shown in Table 2, the minor allele of each polymorphism was found to increase the sensitivity of scattered gastric cancer by more than 40% compared to the majority allele. At this time, the statistical significance level was calculated using the effective degree of freedom (EDF) software to compensate for the increase in error due to multiple testing. The EDF of 23 monobasic polymorphisms considering distributional imbalance was 13.86 and the corrected significance level α was 1- (1-0.05) ^{1 / 13.86} = 0.0037. Statistically significant values (P <0.037) are underlined.

The Relationship between Scattered Gastric Cancer of Monobasic Polymorphism gene Polymorphism function Allele Frequency OR (95% CI) P RHOD rs2282502 Asp88 C> T 0.42 0.95 (0.75-1.18) 0.62 rs10791899 Intergenic A> C 0.22 1.28 (0.99-1.66) 0.060 FBXL11 rs3927807 Intron G> A 0.23 1.29 (1.00-1.67) 0.050 rs1790740 Intergenic T> C 0.23 1.28 (0.99-1.65) 0.056 rs7480390 Intergenic C> G 0.23 1.33 (1.03-1.71) 0.030 TBC1D10C rs10896172 Intron T> C 0.18 1.13 (0.85-1.5) 0.39 KIAA1394 rs1790733 Intron T> C 0.25 1.34 (1.05-1.72) 0.020 RPS6KB2 rs1476792 Intron T> C 0.29 1.44 (1.13-1.82) 0.0026 RPS6KB2 rs917570 Intron C> G 0.18 1.16 (0.87-1.54) 0.32 RPS6KB2 rs55987642 Pro267Leu C> T 0.07 1.08 (0.7-1.67) 0.74 RPS6KB2 rs4930427 Phe269 C> T 0.29 1.43 (1.12-1.81) 0.0033 RPS6KB2 rs1790753 Intron G> A 0.29 1.46 (1.15-1.85) 0.0017 RPS6KB2 rs1790752 Intron C> T 0.29 1.46 (1.15-1.85) 0.0017 RPS6KB2 rs13859 Ala420Val C> T 0.29 1.44 (1.13-1.82) 0.0026 RPS6KB2 rs10274 3 'UTR G> A 0.25 1.36 (1.06-1.75) 0.014 PTPRCAP rs869736 Promoter G> T 0.29 1.45 (1.14-1.83) 0.0020 CORO1B rs872375 Intron G> A 0.29 1.42 (1.12-1.8) 0.0036 CORO1B rs2302264 Intron G> A 0.29 1.43 (1.13-1.81) 0.0028 CORO1B rs1808279 Promoter A> G 0.29 1.47 (1.16-1.86) 0.0013 GPR152 rs1790761 Promoter A> G 0.29 1.44 (1.14-1.82) 0.0024 CABP4 rs17501521 Intron C> T 0.11 1.22 (0.87-1.72) 0.25 AIP rs4084113 Intron G> A 0.18 1.24 (0.94-1.64) 0.12 PITPNM1 rs2276120 Intron C> T 0.18 1.23 (0.93-1.62) 0.15

* OR (Odds ratio): Significant probability (meaning susceptibility to diffuse gastric cancer)

ex) 1.0: There is no difference in polymorphism and cancer incidence.

2.0: Cancer incidence is doubled with polymorphic mutations.

0.5: Cancer incidence is 0.5-fold with polymorphic variation.

* 95% CI (confidence interval): 95% confidence interval

< Example  3> Haplotype ( haplotype ) And Diploid type ( diplotype ) analysis

As a result of analyzing the linkage disequilibrim between the 10 polymorphisms using the Haploview 4.1 program (/www.broad.mit.edu/mpg/haploview/), 10 polymorphisms showed significant association with diffuse gastric cancer. There was a strong association between (R ² = 0.97).

Therefore, the inventors reconstructed haplotypes and diploids using the PHASE 2.1 program (/www.stat.washington.edu/stephens /phase/download.html), and analyzed the relationship between gastric cancer susceptibility.

Specifically, the haplotype is exhibited in the order of the rs1476792, rs4930427, rs1790753, rs1790752, rs13859, rs869736, rs872375, rs2302264, rs1808279 and rs1790761, that is, was named H1 (T-C-G-C-C-G-G-G-A-A) and H2 (C-T-A-T-T-T-A-A-G-G). Because of the strong association between the 10 polymorphisms, only two haplotypes, H1 and H2, were observed at frequencies above 1%. H1 and H2 haploids accounted for 70.3% and 28.3% of the normal haploids, and 61.7% and 35.5% of the haploids of the diffuse gastric cancer patients. The relationship between diplotype and gastric cancer susceptibility was analyzed after adjusting for age and sex.

As a result, as shown in Table 3, H2 had a 43% higher disseminated gastric cancer sensitivity than H1 (OR = 1.43, 95% CI = 1.12-1.82, P = 0.003). In addition, H2 / H2 diplotype and H1 / H2 diplotype showed 150% and 46% increase in diffuse gastric cancer susceptibility compared to H1 / H1 diplotype (OR = 2.50, 95% CI = 1.39-4.47, P = 0.0021; OR = 1.46, 95% CI = 1.04-2.07, P = 0.030). In other words, both haplotype and diploid types were significantly statistically significant.

Haploid and Diploid Analysis division Control group Industrial Gastric Cancer OR (95% CI) P Haploid 2n = 801 2n = 490 H1 (TCGCCGGGAA) 571 (70.3%) 311 (61.7%) One H2 (CTATTTAAGG) 230 (28.3%) 179 (35.5%) 1.43 (1.12-1.82) 0.0034 Diploid n = 399 n = 240 H1 / H1 196 (49.1%) 92 (38.3%) One H1 / H2 176 (44.1%) 118 (49.2%) 1.46 (1.04-2.07) 0.030 H2 / H2 27 (6.8%) 30 (12.5%) 2.50 (1.39-4.47) 0.0021

< Example  4> PTPRCAP  Association of Polymorphism with Gastric Cancer Types

According to Lauren's taxonomy, gastric cancer is divided into intestinal-type and diffuse-type gastric cancer, both of which are known to be histologically and pathologically unique. rs1476792 (+ 112T>C; SEQ ID NO: 82), rs4930427 (+ 401C>T; SEQ ID NO: 83), rs1790753 (+ 301G>A; SEQ ID NO: 84), rs1790752 (+ 401C>T; SEQ ID NO: 85), rs13859 ( + 401C>T; SEQ ID NO: 86), rs869736 (+ 417G>T; SEQ ID NO: 87), rs872375 (+ 101G>A; SEQ ID NO: 88), rs2302264 (+ 301G>A; SEQ ID NO: 89), rs1808279 (+ 220A >G; SEQ ID NO: 90), rs1790761 (+ 218A>G; SEQ ID NO: 91) The polymorphisms were very strongly related to each other (R ² = 0.97) and rs869736 was labeled as only two haplotypes were observed When used as a polymorphism (tagSNP), rs869736 genotyping can be used to identify all other nine polymorphisms.

The present inventors analyzed the genotype of rs869736 polymorphism (G> T) to determine whether the single nucleotide polymorphism is also related to the susceptibility of enteric gastric cancer. In this case, the relationship between genotype and gastric cancer was described by the age and sex. Statistically significant results are underlined.

As a result, as shown in Table 4, rs869736 , a promoter polymorphism of PTPRCAP, showed a specific relationship to susceptibility to diffuse gastric cancer. In other words, the T allele of rs188703 significantly increased the sensitivity of diffuse gastric cancer by 1.45 times (OR = 1.45, 95% CI = 1.14-1.83, P = 0.0020), but found a significant correlation with the sensitivity of intestinal gastric cancer. It wasn't. In addition, the GT and TT genotypes were found to be 1.45 times higher and 2.47 times higher, respectively, when compared with the GG genotypes.

Association between intestinal gastric and diffuse gastric cancer and rs869736 polymorphism Control group Stomach stomach cancer group Intestinal gastric cancer 2n = 812 2n = 504 OR (95% CI) P 2n = 356 OR (95% CI) P Allele G 577 (71.1%) 317 (62.9%) One 236 (66.3%) One T 235 (28.9%) 187 (37.1%) 1.45 (1.14-1.83) 0.0020 120 (33.7%) 1.25 (0.96-1.63) 0.10 genotype n = 406 n = 252 n = 178 GG 198 (48.8%)  96 (38.1%) One 76 (42.7%) One GT 181 (44.6%) 125 (49.6%) 1.45 (1.04-2.03) 0.031 84 (47.2%) 1.03 (0.68-1.56) 0.87 TT  27 (6.7%)  31 (12.3%) 2.47 (1.39-4.40) 0.0021 18 (10.1%) 1.52 (0.72-3.20) 0.30

< Example  5> Promoter activity measurement

As a result of the above example, the promoters of the PTPRCAP, CORO1B and GPR152 genes were found to have a polymorphism showing a significant correlation with diffuse gastric cancer. Therefore, after transfecting the gastric cancer cell line by cloning the promoter region including monobasic polymorphism, luciferase activity was measured to investigate the effect of changes in DNA sequence on the promoter activity of each gene.

Specifically, the PCR reaction was a 50 μl solution with 400 μM PCR primer pairs (Table 5) added to a 10 ng genomic DNA, 1 × buffer, 200 μM dNTP mixture, 1.25 unit Pfu DNA polymerase (Solgent, Korea) mixture. Was performed in. PCR products were purified using AccuPrep ^® gel purification kit (Bionia, Korea), and then digested with Kpn I and Xho I restriction enzymes and inserted into pGL3 basic vector (Promega, USA). Recombinant plasmids were identified by sequencing.

PCR primer sequences used for promoter cloning gene Forward primer Reverse primer Amplification size PTPRCAP CAGC GGTACC GTCAGTTCCCACCCCCAC: SEQ ID NO: 68 GGGC CTCGAG CTCCAGCTCTGGCTGTGTC: SEQ ID NO: 69 610 bp CORO1B TTTA GGTACC GCATGGTGTCTCACGCCTG: SEQ ID NO: 70 GATC CTCGAG TCTGGGAAGCAGGAAGCAGG: SEQ ID NO: 71 800 bp GPR152 GGC GGTACC GGTAAGCCAGGCCTCACTGGTC: SEQ ID NO: 72 GGC CTCGAG AGAGTCCTGCTGGACACGGAGTG: SEQ ID NO: 73 1772 bp

* Kpn I and Xho I recognition sequences are underlined.

In addition, 1 × 10 ⁵ MKN28 cells (Korea Cell Line Bank) were incubated for 12 hours in a 12-well tissue culture dish, and then 1 μg of recombinant plasmid prepared by allele and 50 ng of pRL-CMV vector (Promega, USA). the Lipofectamine ^TM Was mixed with LTX Reagent (Invitrogen, USA) sikyeotgo co-transfection in MKN28 cells, the luciferase activity was measured using Dual-luciferase reporter ^® test system (Promega, USA) after 36 hours. Each experiment was repeated three times.

As a result, it was confirmed that even with the case of PTPRCAP rs869736 (-309G> T) polymorphism of T 1.55 times stronger promoter activity as compared to the allele G allele as shown in 2 (P = 0.00039, ANOVA) .

On the other hand, GPR152 The promoter inserted plasmid did not show luciferase activity and CORO1B The promoter strongly expressed luciferase, but there was no difference in promoter activity between alleles.

< Example  6> DNA Protein binding force measurement

PTPRCAP DNA-protein binding differences between alleles were examined using 29 nt around the promoter polymorphism rs869736 as a probe.

Specifically, annealing of complementary single-stranded DNA synthesized by allele of Table 6 was made to make a double-stranded DNA probe, and the 5 'end was labeled with [g- ³² P] dATP (PerkinElmer, USA). Strand probes were made. 8 μg MKN28 nuclear extract (Schreiber E et al . , Nucleic Acids Res ., 21: 253-258, 1993) and 0.6 μg of poly (dI-dC), 1X EMSA reaction buffer (10 mM HEPES-KOH, pH 7.9, 60 mM KCl, 1 mM EDTA, 10% glycerol, 10 mM MgCl ₂ , 200 mM dithiothreitol) was mixed and reacted at room temperature for 20 minutes. 80 fmole probe was added to the mixture, followed by further reaction for 20 minutes, followed by electrophoresis on 6% polyacrylamide gel, and radioactive image was obtained by BAS-3000 (Fujifilm LifeScience, Japan). At this time, protein binding was competitive by further adding a 200-fold excess of DNA G probe or T probe that was not radiolabeled.

DNA sequence of EMSA probe Allele Forward Reverse G AACCTGGAGACAGA G GATGTCACAGGAGT: SEQ ID NO: 74 ACTCCTGTGACATC C TCTGTCTCCAGGTT: SEQ ID NO: 75 T AACCTGGAGACAGA T GATGTCACAGGAGT: SEQ ID NO: 76 ACTCCTGTGACATC A TCTGTCTCCAGGTT: SEQ ID NO: 77

* The location of the rs869736 polymorphism is underlined.

As a result, as shown in Figure 3 PTPRCAP The T allele of the rs869736 polymorphism at the -309 position of the promoter was much more strongly bound to the MKN28 nuclear extract than the G allele. At this time, the labeled T probe retained the binding strength of the protein even when it competed with the 200-fold excess of DNA G probe that was not labeled with radioactivity, but the unlabeled 200-fold excess of T probe did not bind the protein with the labeled T probe. Completely inhibited.

< Example  7> In vivo ( in vivo ) Measurement of gene expression level

In vivo PTPRCAP according to the monobasic polymorphism rs869736 allele Changes in mRNA expression levels were examined by real-time PCR.

Specifically, DNA was isolated from twelve B cell lines (obtained from Hanyang University Rheumatic Hospital) and analyzed by rs869736 genotype, which was classified into three groups, GG, GT and TT. In addition, the RNA was isolated using the ^{NucleoSpin ® (Macherey-Nagel GmbH &} Co., Germany) from the said sorted cell line was synthesized cDNA using Oligo (dT) primer and reverse transcriptase (Promega, Madison, WI). Primers for amplifying a portion of the mRNA and GAPDH PTPRCAP pair to prepare the (Table 6) Bio-Rad iQ ^TM ICycleriQ ^TM after mixing with SYBR ^ㄾ Green Supermix (Bio- ^Rad.USA ) Real-time PCR was performed on 5 machines (Bio-Rad. USA). After performing initial denaturation at 95 degreeC for 1 minute, the cycle of 95 degreeC 10 second, 57 degreeC 20 second, and 72 degreeC 20 second was repeated 40 times. The relative amount of PTPRCAP was measured based on the expression level of GAPDH . Each experiment was repeated three times.

Real Time PCR Primer Sequence gene Forward Reverse Amplification size PTPRCAP AGCTGGGGTCCACAGACAA: SEQ ID NO: 78 GACGCCTCTCCACATTGCT: SEQ ID NO: 79 127 bp GAPDH CAGCCTCAAGATCATCAGCA: SEQ ID NO: 80 TGTGGTCATGAGTCCTTCCA: SEQ ID NO: 81 106 bp

As a result, the more the number of the T allele of the rs869736 polymorphism increase as shown in Figure 4 PTPRCAP It was confirmed that the amount of expression significantly increased (P = 0.0060). With the GT and TT genotypes, PTPRCAP expression increased by 35% and 18%, respectively, compared to the GG genotype.

In conclusion, we found that RPS6KB2 , PTPRCAP , CORO1B and GPR152 Rs1476792, rs4930427, rs1790753, rs1790752, rs13859, rs869736, rs872375, rs2302264, rs1808279 and rs1790761 polymorphisms, haploids and diploids of the genes were found to be significantly associated with susceptibility to diffuse gastric cancer. The polymorphism was not related to the susceptibility of intestinal gastric cancer. Especially PTPRCAP T allele of rs869736 polymorphism was present in the -309 position of the promoter binding force of the promoter activity and protein appeared stronger than the G allele in vivo PTPRCAP It was confirmed that there is a significant correlation with the expression level. Thus, the polymorphism, haploid and diploid of the present invention can be usefully used for predicting susceptibility of scattered gastric cancer.

1 is a diagram showing the relationship between the location of single nucleotide polymorphism and scattered gastric cancer susceptibility in the 26 kb region containing the RPS6KB2, PTPRCAP, CORO1B and GPR152 gene.

2 is a diagram showing the effect of rs869736 (-309G> T), the promoter polymorphism of PTPRCAP on promoter activity.

Figure 3 is a diagram showing the results of the eletrophoretic mobility shift assay (EMSA) measuring the DNA-protein binding capacity of alleles of the rs869736 polymorphism.

4 PTPRCAP in vivo in B cell line It is a real-time PCR result measuring the expression amount.

<110> Korea Advanced Instititue of Science and Technology <120> Polymorphic markers predicting susceptibility to diffuse-type          gastric cancer and the prediction method according using the same <130> 9P-02-35 <160> 91 <170> Kopatentin 1.71 <210> 1 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs2282502 Forward PCR Primer <400> 1 acgttggatg tggtgacatc gaagcaaagc 30 <210> 2 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs2282502 Reverse PCR Primer <400> 2 acgttggatg agggcaagat gactatgacc 30 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> rs2282502 Ext Primer <400> 3 cggcccctgt tctaccctga 20 <210> 4 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs10791899 Forward PCR Primer <400> 4 acgttggatg agtgtccagt ggtctgtaac 30 <210> 5 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs10791899 Reverse PCR Primer <400> 5 acgttggatg ggaaggctat ctgatcactc 30 <210> 6 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs10791899 Ext Primer <400> 6 gagtcagtga cagggctgg 19 <210> 7 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs3927807 Forward PCR Primer <400> 7 acgttggatg tccaacccat ttgtccactg 30 <210> 8 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs3927807 Reverse PCR Primer <400> 8 acgttggatg ttacctaggt gtcctcctag 30 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> rs3927807 Ext Primer <400> 9 tcctaggtca ggatcctgtt 20 <210> 10 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790740 Forward PCR Primer <400> 10 acgttggatg agctcccagg taatacatgg 30 <210> 11 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790740 Reverse PCR Primer <400> 11 acgttggatg tatatgagta gcctcgctcc 30 <210> 12 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> rs1790740 Ext Primer <400> 12 acttccaaac aagctctcaa g 21 <210> 13 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs7480390 Forward PCR Primer <400> 13 acgttggatg tgttcacaac accttccacc 30 <210> 14 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs7480390 Reverse PCR Primer <400> 14 acgttggatg cggaaggact gtggaagttg 30 <210> 15 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> rs7480390 Ext Primer <400> 15 gttgtttttc tctttcaaaa gcc 23 <210> 16 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs10896172 Forward PCR Primer <400> 16 acgttggatg tagcccaaac tcacactgtg 30 <210> 17 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs10896172 Reverse PCR Primer <400> 17 acgttggatg aagatcctag gcagaactgc 30 <210> 18 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs10896172 Ext Primer <400> 18 tcttccctaa gccaggagc 19 <210> 19 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790733 Forward PCR Primer <400> 19 acgttggatg ctgccctttc tgtagaaggg 30 <210> 20 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> rs1790733 Reverse PCR Primer <400> 20 acgttggatg tttctgcctg tgctgctgga g 31 <210> 21 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> rs1790733 Ext Primer <400> 21 gtccagagcc cgggtgagtg t 21 <210> 22 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1476792 Forward PCR Primer <400> 22 acgttggatg acccagatcc ttctcagatc 30 <210> 23 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1476792 Reverse PCR Primer <400> 23 acgttggatg agaatcggga gaaaaggctg 30 <210> 24 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs1476792 Ext Primer <400> 24 gggtgagggt gggatcaga 19 <210> 25 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs917570 Forward PCR Primer <400> 25 acgttggatg agtgagtgag ggtcgtgttg 30 <210> 26 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs917570 Reverse PCR Primer <400> 26 acgttggatg taatgaggac aaggctccag 30 <210> 27 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> rs917570 Ext Primer <400> 27 gacaaggctc cagtgctccc ca 22 <210> 28 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs55987642 Forward PCR Primer & rs4930427 Reverse PCR Primer <400> 28 acgttggatg tgcccctgat gatcttatcc 30 <210> 29 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs4930427 Forward PCR Primer & rs55987642 Reverse PCR Primer <400> 29 acgttggatg acaaggctcc tctcaccttc 30 <210> 30 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> rs55987642 Ext Primer <400> 30 cttcctcctc ctccagc 17 <210> 31 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> rs4930427 Ext Primer <400> 31 ttccggttct ctgcggt 17 <210> 32 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790753 Forward PCR Primer <400> 32 acgttggatg tcattcccag aggcaaactg 30 <210> 33 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790753 Reverse PCR Primer <400> 33 acgttggatg attctgcacg tgttcctgag 30 <210> 34 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> rs1790753 Ext Primer <400> 34 caaactgcac aggccggg 18 <210> 35 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790752 Forward PCR Primer <400> 35 acgttggatg ttgatgctgt ccaggacaga 30 <210> 36 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790752 Reverse PCR Primer <400> 36 acgttggatg atcgtgacta aggatggcag 30 <210> 37 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs1790752 Ext Primer <400> 37 gtcgcatggc cctgcctcc 19 <210> 38 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> rs13859 Forward PCR Primer <400> 38 acgttggatg ttctccttcc agcccaagc 29 <210> 39 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs13859 Reverse PCR Primer <400> 39 acgttggatg tccctaaccc agccacacac 30 <210> 40 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> rs13859 Ext Primer <400> 40 cctcagtacc tgacgggg 18 <210> 41 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs10274 Forward PCR Primer <400> 41 acgttggatg tgaaagtgtg tgtctgctgg 30 <210> 42 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs10274 Reverse PCR Primer <400> 42 acgttggatg ttaatcttcc acgggagcag 30 <210> 43 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> rs10274 Ext Primer <400> 43 gggagcagtt gagcgcgggg 20 <210> 44 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs869736 Forward PCR Primer <400> 44 acgttggatg ttctgcacat gtgtgactcc 30 <210> 45 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs869736 Reverse PCR Primer <400> 45 acgttggatg ttctaaaagc caggctgacc 30 <210> 46 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> rs869736 Ext Primer <400> 46 ggaaacctgg agacaga 17 <210> 47 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> rs872375 Forward PCR Primer <400> 47 acgttggatg tgcatcacct cctccagctt c 31 <210> 48 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs872375 Reverse PCR Primer <400> 48 acgttggatg ttgggagggc tatggcttag 30 <210> 49 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs872375 Ext Primer <400> 49 ctacccctgc ttcatgtcc 19 <210> 50 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs2302264 Forward PCR Primer <400> 50 acgttggatg atcctccact tccagtcctc 30 <210> 51 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs2302264 Reverse PCR Primer <400> 51 acgttggatg tgagaactgt cacgaggcag 30 <210> 52 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs2302264 Ext Primer <400> 52 gtctagccac cttaggggt 19 <210> 53 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> rs1808279 Forward PCR Primer <400> 53 acgttggatg gggaaatcga gaccatcct 29 <210> 54 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> rs1808279 Reverse PCR Primer <400> 54 acgttggatg caagaaattc accccagtag c 31 <210> 55 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs1808279 Ext Primer <400> 55 gtagctggga ctacaggct 19 <210> 56 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790761 Forward PCR Primer <400> 56 acgttggatg ctggggctct gatccaatag 30 <210> 57 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs1790761 Reverse PCR Primer <400> 57 acgttggatg gccacttggc ctttagtttg 30 <210> 58 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs1790761 Ext Primer <400> 58 tttggtgccc tccgtaccc 19 <210> 59 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs17501521 Forward PCR Primer <400> 59 acgttggatg tttcttccta ggtgcagagc 30 <210> 60 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs17501521 Reverse PCR Primer <400> 60 acgttggatg tgagggcata aggtctgaag 30 <210> 61 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> rs17501521 Ext Primer <400> 61 ggcataaggt ctgaagccca ag 22 <210> 62 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> rs4084113 Forward PCR Primer <400> 62 acgttggatg atccgcaggt ggactgctg 29 <210> 63 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs4084113 Reverse PCR Primer <400> 63 acgttggatg aaaggagacc cagggtactg 30 <210> 64 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> rs4084113 Ext Primer <400> 64 acaggttttc ttgtctctgt cc 22 <210> 65 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> rs2276 120 Forward PCR Primer <400> 65 acgttggatg tgcgcaaaac tgtgatgccc 30 <210> 66 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> rs2276 120 Reverse PCR Primer <400> 66 acgttggatg aaggaagggg cagacagaga c 31 <210> 67 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> rs2276120 Ext Primer <400> 67 cagacagaga ctagaggcg 19 <210> 68 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> PTPRCAP Forward Primer <400> 68 cagcggtacc gtcagttccc acccccac 28 <210> 69 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> PTPRCAP Reverse Primer <400> 69 gggcctcgag ctccagctct ggctgtgtc 29 <210> 70 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> CORO1B Forward Primer <400> 70 tttaggtacc gcatggtgtc tcacgcctg 29 <210> 71 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> CORO1B Reverse Primer <400> 71 gatcctcgag tctgggaagc aggaagcagg 30 <210> 72 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> GPR152 Forward Primer <400> 72 ggcggtaccg gtaagccagg cctcactggt c 31 <210> 73 <211> 32 <212> DNA <213> Artificial Sequence <220> <223> GPR152 Reverse Primer <400> 73 ggcctcgaga gagtcctgct ggacacggag tg 32 <210> 74 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> G Forward <400> 74 aacctggaga cagaggatgt cacaggagt 29 <210> 75 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> G Reverse <400> 75 actcctgtga catcctctgt ctccaggtt 29 <210> 76 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> T Forward <400> 76 aacctggaga cagatgatgt cacaggagt 29 <210> 77 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> T Reverse <400> 77 actcctgtga catcatctgt ctccaggtt 29 <210> 78 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> PTPRCAP Forward <400> 78 agctggggtc cacagacaa 19 <210> 79 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> PTPRCAP Reverse <400> 79 gacgcctctc cacattgct 19 <210> 80 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH Forward <400> 80 cagcctcaag atcatcagca 20 <210> 81 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH Reverse <400> 81 tgtggtcatg agtccttcca 20 <210> 82 <211> 348 <212> DNA <213> Artificial Sequence <220> <223> rs1476792 <220> <221> primer_bind <222> (76) .. (96) <223> forward primer binding <220> <221> primer_bind (222) (152) .. (162) <223> reverse primer binding <220> <221> allele <222> (112) <223> [T / C] <400> 82 tggagccgat cctgtcaccc agccgaggcc ggagcggcgg ctccgcacgc ccagagcggg 60 ctccgactct ttgcagaccc agatccttct cagatcccgg tctctattaa gytctgatcc 120 caccctcacc ccgacctctc ttccagaacc ccagcctttt ctcccgattc tccctttcct 180 gccttcggtt tcttcccaat tcttacccat cccctactag ctgccatccc tgacaccctt 240 ctctcctggg ccacgcagtc caacctgaac gggagcgggg aggtatcctg gcaccttcct 300 tggctcttac ccctcggttt ctcacaggac gcatgtcccc ttgccgag 348 <210> 83 <211> 801 <212> DNA <213> Artificial Sequence <220> <223> rs4930427 <220> <221> allele <222> (401) <223> [C / T] <220> <221> primer_bind (222) (361) .. (380) <223> forward primer binding <220> <221> primer_bind <222> (428) .. (447) <223> reverse primer binding <400> 83 tcaggccaca tcaaactgac cgactttgga ctctgcaagg agtctatcca tgagggcgcc 60 gtcactcaca ccttctgcgg caccattgag tacatgtaag tggcacctgg ctggcccagg 120 ggtcgggagg acagcccgaa ggggcacggc ctgactgaca gttccacctg gaccccaggg 180 cccctgagat tctggtgcgc agtggccaca accgggctgt ggactggtgg agcctggggg 240 ccctgatgta cgacatgctc actggatcgg caagtccagc ccccggggag gaggaggggc 300 aggggcagag gtgggagtag cccccctcct ggggcaaggg cagggcctgg tgggaggccc 360 acaaggctcc tctcaccttc ctcctcctcc agccgccctt yaccgcagag aaccggaaga 420 aaaccatgga taagatcatc aggggcaagc tggcactgcc cccctacctc accccagatg 480 cccgggacct tgtcaaaaag gtgcagctcc cttctctctt ctccggggcc ctgccagcca 540 ttctgcacgt gttcctgagt ctctctgggc tgtggggaag ccagggccac cccggcctgt 600 gcagtttgcc tctgggaatg aaaggagccc ctcccttgaa gtcagggatt gagcccaggt 660 ctcagccctg tcacagacca gctgctgccc tggcccagtc cttaggctga gtcctaacca 720 gtgacacgct tgtgatgagc tggccacact tccgtcaaag gcgagcatcg gaggtgttag 780 ggggaggccg gacagccaca t 801 <210> 84 <211> 516 <212> DNA <213> Artificial Sequence <220> <223> rs1790753 <220> <221> primer_bind (222) (270) .. (289) <223> forward primer binding <220> <221> primer_bind (222) (332) .. (351) <223> reverse primer binding <220> <221> allele <222> (301) <223> [G / A] <400> 84 caatggagcc accttctcca caaaggcttt gcagaggctc ctgggccctg gcattgcccc 60 agggcgcgtt ggtgaggcgc caactcccca tgtggctgtc cggcctcccc ctaacacctc 120 cgatgctcgc ctttgacgga agtgtggcca gctcatcaca agcgtgtcac tggttaggac 180 tcagcctaag gactgggcca gggcagcagc tggtctgtga cagggctgag acctgggctc 240 aatccctgac ttcaagggag gggctccttt cattcccaga ggcaaactgc acaggccggg 300 rtggccctgg cttccccaca gcccagagag actcaggaac acgtgcagaa tggctggcag 360 ggccccggag aagagagaag ggagctgcac ctttttgaca aggtcccggg catctggggt 420 gaggtagggg ggcagtgcca gcttgcccct gatgatctta tccatggttt tcttccggtt 480 ctctgcggtg aagggcggct ggaggaggag gaaggt 516 <210> 85 <211> 691 <212> DNA <213> Artificial Sequence <220> <223> rs1790752 <220> <221> allele <222> (401) <223> [C / T] <220> <221> primer_bind (222) (352) .. (371) <223> forward primer binding <220> <221> primer_bind <222> (430) .. (450) <223> reverse primer binding <400> 85 aggcagaata agagcctcct aggccctgcc agaggctccc agcactcagt cagggaaggc 60 agcctttccc acctgcccag gcacacaggc cgcgggctcc acaaactccc atccaggcag 120 cctggccaca aggggtgtag gaactgaggt ccccatgata gacacagcaa ccgaagccaa 180 cactggccga cagacgtggc caaggcaccc aaggctggag ctggcatcct gcctgccagc 240 gtccctaacc cagccacaca cccccacgtc cctcagtacc tgacgggggc ccgggggcta 300 ctgttgaggc gcctgggtga gcgcagcttg ggctggaagg agaagccctc cttgatgctg 360 tccaggacag acggcgccac gtatgtgaag ccctgggggg yggaggcagg gccatgcgac 420 actcagtgcc tgccatcctt agtcacgatc cgtgccctgg tcccacaggc ctcaggcccc 480 cgcactcacc aggaaggcct ggttggcact ctcgctgagg gctgtgtcat caggactgtc 540 caccggcgtc tgccgtgtga agcgggtatc aaactggctc acgtcctcct ctgactgctg 600 tgggccgacc agagtgggga ggggtcagag ggcaccaaga tgcaggttct ccacttgcca 660 cccgccaccg gccactggcc accagccctg c 691 <210> 86 <211> 632 <212> DNA <213> Artificial Sequence <220> <223> rs13859 <220> <221> allele <222> (401) <223> [C / T] <220> <221> primer_bind (222) (346) .. (364) <223> forward primer binding <220> <221> primer_bind (222) (429) .. (449) <223> reverse primer binding <400> 86 agggctggtg gccagtggcc ggtggcgggt ggcaagtgga gaacctgcat cttggtgccc 60 tctgacccct ccccactctg gtcggcccac agcagtcaga ggaggacgtg agccagtttg 120 atacccgctt cacacggcag acgccggtgg acagtcctga tgacacagcc ctcagcgaga 180 gtgccaacca ggccttcctg gtgagtgcgg gggcctgagg cctgtgggac cagggcacgg 240 atcgtgacta aggatggcag gcactgagtg tcgcatggcc ctgcctccgc cccccagggc 300 ttcacatacg tggcgccgtc tgtcctggac agcatcaagg agggcttctc cttccagccc 360 aagctgcgct cacccaggcg cctcaacagt agcccccggg yccccgtcag gtactgaggg 420 acgtgggggt gtgtggctgg gttagggacg ctggcaggca ggatgccagc tccagccttg 480 ggtgccttgg ccacgtctgt cggccagtgt tggcttcggt tgctgtgtct atcatgggga 540 cctcagttcc tacacccctt gtggccaggc tgcctggatg ggagtttgtg gagcccgcgg 600 cctgtgtgcc tgggcaggtg ggaaaggctg cc 632 <210> 87 <211> 689 <212> DNA <213> Artificial Sequence <220> <223> rs869736 <220> <221> allele <222> (417) <223> [G / T] <220> <221> primer_bind (222) (350) .. (369) <223> reverse primer binding <220> <221> primer_bind (222) (427) .. (446) <223> forward primer binding <400> 87 tgcggcacgc atggtagaac ggggatgcgt agggccacag ccacacgcca ccttcatctc 60 ctccgccgcc cccttcccac tcagcttctg ccagcgggtc gcaccgggct agctggctgc 120 ccagagcctc tgaggcagcg caggggtcag ttcccacccc cacccgtccc aggcccaggc 180 cgaagccagc gcccagcttt cctcactgtt cctgtggagg atgtctacgc ccaggcgagc 240 tcctcgacct ctgagggacc atctccccga ccactgccca gccctctgct ccctccccag 300 aggaggcggg agggtgggct ctatattttc attccaaata aaattctctt tctaaaagcc 360 aggctgacct gctgctgcaa gggtggggct gagaagtctg gaaacctgga gacagakgat 420 gtcacaggag tcacacatgt gcagaaggtc tgggggcagt gagcagcccc acaggcattg 480 ctcccctgga ttgtcaggca gggaaactga ggcagaagac ctgagaacac atgcaaggct 540 gcatccagct tcaagttggt gctgcttctt ccttggagga caggcccggc agcccagcct 600 cctccagaga gactggggag ggtctggtgt ggaccagggg tcctgcagca gggaggggca 660 ggtggggtat gtgggcagga agcggaagc 689 <210> 88 <211> 232 <212> DNA <213> Artificial Sequence <220> <223> rs872375 <220> <221> allele <222> (101) <223> [G / A] <220> <221> primer_bind (222) (67) .. (87) <223> forward primer binding <220> <221> primer_bind <141> (141) .. (160) <223> reverse primer binding <400> 88 ctgctcctcc agcggcagat gcggtcgccc tgctccttga ccagcgccct cagggcccgc 60 agctcctgca tcacctcctc cagcttccca gcctcctgtg rggacatgaa gcaggggtag 120 ggggcggtgg tcaggggctg ctaagccata gccctcccaa acccaccact accccagaga 180 gggacagcga atggctgaag cccacacagc aggccagggc cacacctggg gc 232 <210> 89 <211> 519 <212> DNA <213> Artificial Sequence <220> <223> rs2302264 <220> <221> allele <222> (301) <223> [G / A] <220> <221> primer_bind 222 (260) .. (279) <223> forward primer binding <220> <221> primer_bind (222) (332) .. (351) <223> reverse primer binding <400> 89 ggcatctgtc cagctcactg cccacaaacc atactaggtc atgttccatt cacaggcctc 60 gccctggtca caactgcatg gcccgcttgc tggagaaagg gccaagtgag ccgagggacg 120 ggcggcctca cctttcttgg cacagtcatg acgatgggct cacacttgcg ctcatgcagt 180 ttgtagaacc tggggatgca aggaggagcc acgggtggaa ccctcaccgc cccccccacc 240 caccgccagc tctcctggca tcctccactt ccagtcctca ccccaggacc tccgcaggcc 300 racccctaag gtggctagac ccccacacgg gctgcctcgt gacagttctc atggcccgcc 360 gggcctccct ggcgcaaggt ttcctgctcc caagcagcct ccaatgacct gacctctcac 420 cttagatgcc cctatccccg agtggcctcg gtagccctct taccgggcga tctcgcactt 480 gctgacctcc aggccccgct tgggcatgct gcccatacc 519 <210> 90 <211> 345 <212> DNA <213> Artificial Sequence <220> <223> rs1808279 <220> <221> allele <222> (220) <223> [A / G] <220> <221> primer_bind <222> (138) .. (156) <223> forward primer binding <220> <221> primer_bind <235> (235) .. (255) <223> reverse primer binding <400> 90 aaaaaaaaaa ccaccccaac acctgctgtt gttttcttta cattgttaac caagagcatg 60 aaatttaggc cgggcatggt gtctcacgcc tgtaatccca gcactttggg aggccgaggc 120 gggcggatca cgaggtcggg aaatcgagac catcctggct aacatggtga aaccccgtct 180 ctactaaaca tacaaaaaat tagccgggcg tggtagtatr agcctgtagt cccagctact 240 ggggtgaatt tcttgaacct gggagggcgg aggttgcagt gggccgagat cgcgccactg 300 cactccagcc tgggtgacaa aaactccgtc tcaaaaaaaa aaaaa 345 <210> 91 <211> 345 <212> DNA <213> Artificial Sequence <220> <223> rs1790761 <220> <221> allele <222> (218) <223> [A / G] <220> <221> primer_bind (222) (155) .. (174) <223> forward primer binding <220> <221> primer_bind (234) (234) <223> reverse primer binding <400> 91 tgccgggtgc cacaaagcag gccccagtga gggccggggg gacagctgga gtgctgggca 60 ggcaggcacg ccctgctcct gctccttcca cccatcggcc tctgcctccc aggtaagcca 120 ggcctcactg gtcagggccc cagtctcggg gtgcctgggg ctctgatcca atagggaatg 180 gagacagcag agggggtcag cctgaggagg aaccctgrgg gtacggaggg caccaaacta 240 aaggccaagt ggctggagcc gtgggccgtg ggcaggggcc agcccttcag ggcatccgtt 300 ccctccccag actataccac cacctgggct ctcatcgccc tcaaa 345  

Claims (14)

Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), G or T, and the +417 th base Regarding, the kit for predicting interstitial gastric cancer susceptibility comprising a probe or primer pair capable of detecting the polymorphic site. The method of claim 1, 1) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the +112 th base, which is the polymorphic site of rs1476792 (SEQ ID NO: 82), is T or C, and includes the +112 th base Polynucleotides; 2) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is C or T and comprises the +401 th base Polynucleotides; 3) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the +301 th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is G or A and comprises the +301 th base Polynucleotides; 4) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +401 th base, which is the polymorphic site of rs1790752 (SEQ ID NO: 85), is C or T, and the +401 th base Polynucleotides; 5) Scattered gastric cancer-related association of the polymorphic site of rs13859 (SEQ ID NO: 86), where the +401 th base is C or T and 20 to 100 consecutive nucleic acid molecules comprising the +401 th base or complementary nucleic acid molecules Polynucleotides; 6) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is G or A; Polynucleotides; 7) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +301 th base, which is the polymorphic site of rs2302264 (SEQ ID NO: 89), is G or A, and the +301 th base Polynucleotides; 8) Scattered gastric cancer-related, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules of which the + 220th base, which is the polymorphic site of rs1808279 (SEQ ID NO: 90), is A or G, and includes the + 220th base Polynucleotides; And 9) Scattered gastric cancer-related association of the polymorphic site of rs1790761 (SEQ ID NO: 91) with + 21st base A or G and 20-100 consecutive nucleic acid molecules comprising the + 218th base or complementary nucleic acid molecules Polynucleotides; For any one or more polynucleotides selected from the group consisting of, characterized in that it further comprises a probe or primer pair that can detect the polymorphic site, interstitial gastric cancer susceptibility prediction kit. The scattered gastric cancer according to claim 1 or 2, wherein the probe is 15 to 50mers long selected within the polynucleotide to comprise 15 to 50 consecutive bases comprising the polymorphic site. Susceptibility Prediction Kit. The method of claim 2, wherein the primer pair is Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules thereof, wherein the +112 th base, which is the polymorphic site of rs1476792 (SEQ ID NO: 82), is T or C and includes the +112 th base Primer pair 1 consisting of a forward primer as set out in SEQ ID NO: 22 and a reverse primer as set out in SEQ ID NO: 23 for detecting a; Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is C or T, and the +401 th base Primer pair 2 consisting of a forward primer as set out in SEQ ID NO: 29 and a reverse primer as set out in SEQ ID NO: 28 for detecting a; Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +301 th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is G or A, and the +301 th base Primer pair 3, consisting of a forward primer as set out in SEQ ID NO: 32 and a reverse primer as set out in SEQ ID NO: 33 for detecting a; Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +401 th base, which is the polymorphic site of rs1790752 (SEQ ID NO: 85), which is C or T, and which comprises the +401 th base Primer pair 4 consisting of a forward primer as set out in SEQ ID NO: 35 and a reverse primer as set out in SEQ ID NO: 36 for detecting a; Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +401 th base, which is the polymorphic site of rs13859 (SEQ ID NO: 86), is C or T, and the +401 th base Primer pair 5 consisting of a forward primer set forth in SEQ ID NO: 38 and a reverse primer set forth in SEQ ID NO: 39 for detecting a; Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), G or T, and the +417 th base Primer pair 6 consisting of a forward primer as set out in SEQ ID NO: 44 and a reverse primer as set out in SEQ ID NO: 45 for detecting a; Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is G or A, and the +101 th base Primer pair 7 consisting of a forward primer as depicted in SEQ ID NO: 47 and a reverse primer as depicted in SEQ ID NO: 48 for detecting a; Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +301 th base, which is the polymorphic site of rs2302264 (SEQ ID NO: 89), is G or A, and the +301 th base Primer pair 8 consisting of a forward primer as set out in SEQ ID NO: 50 and a reverse primer as set out in SEQ ID NO: 51 for detecting a; Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +220 th base, which is the polymorphic site of rs1808279 (SEQ ID NO: 90), A or G, and the +220 th base Primer pair 9 consisting of a forward primer as set out in SEQ ID NO: 53 and a reverse primer as set out in SEQ ID NO: 54 for detecting a; And Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +218 th base, which is the polymorphic site of rs1790761 (SEQ ID NO: 91), A or G, and the +218 th base Primer pair 10, characterized in that it consists of a forward primer set forth in SEQ ID NO: 56 and a reverse primer set forth in SEQ ID NO: 57 for detecting a; Dispersed gastric cancer susceptibility prediction kit, characterized in that selected from the group consisting of. The method according to claim 1 or 2, wherein the primer pair is composed of 15 to 50 consecutive bases comprising the polymorphic site, characterized in that it has at least one oligonucleotide having the base of the polymorphic site 3 'end. A kit for disseminated gastric cancer susceptibility prediction. Microarray for predicting interstitial gastric cancer susceptibility in which scattered gastric cancer-related oligonucleotides composed of 5 to 25 consecutive nucleic acid molecules or complementary nucleic acid molecules containing the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87) . The method according to claim 6, 1) Scattered gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +112 th base, which is the polymorphic site of rs1476792 (SEQ ID NO: 82); 2) scattered gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83); 3) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +301 th base, the polymorphic site of rs1790753 (SEQ ID NO: 84); 4) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +401 th base, the polymorphic site of rs1790752 (SEQ ID NO: 85); 5) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +401 th base, the polymorphic site of rs13859 (SEQ ID NO: 86); 6) interspersed gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88); 7) interspersed gastric cancer-related oligonucleotides consisting of 5 to 25 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +301 th base, which is the polymorphic site of rs2302264 (SEQ ID NO: 89); 8) interspersed gastric cancer-related oligonucleotide consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +220 th base, which is the polymorphic site of rs1808279 (SEQ ID NO: 90); And 9) Scattered gastric cancer-related oligonucleotides consisting of 5-25 consecutive nucleic acid molecules or nucleic acid molecules complementary thereto comprising the +218 th base, the polymorphic site of rs1790761 (SEQ ID NO: 91); Dispersed gastric cancer susceptibility prediction microarray, characterized in that any one or more oligonucleotides additionally selected from the group consisting of. The +112 th base, which is the polymorphic site of rs1476792 (SEQ ID NO: 82), a monobasic polymorphism marker present in the human genome 11q13 region, is C; ② the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is T; ③ The + 301th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is A; ④ the +401 th base which is the polymorphic site of rs1790752 (SEQ ID NO: 85) is T; The polymorphic site of rs13859 (SEQ ID NO: 86) is the +401 base; ⑥ the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), is T; ⑦ the +101 th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is A; ⑧ the +301 th base which is the polymorphic site of rs2302264 (SEQ ID NO: 89) is A; The polymorphic site of rs1808279 (SEQ ID NO: 90) at the +220 th base is G; And a haplotype marker for predicting diffuse gastric cancer susceptibility in which the +218 th base, which is the polymorphic site of rs1790761 (SEQ ID NO: 91), is G. The +112 th base, which is the polymorphic site of rs1476792 (SEQ ID NO: 82), a single nucleotide polymorphism marker present in the human genome 11q13 region, is T; ② the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is C; ③ The + 301th base, which is the polymorphic site of rs1790753 (SEQ ID NO: 84), is G; ④ the +401 th base which is the polymorphic site of rs1790752 (SEQ ID NO: 85) is C; The polymorphic site of rs13859 (SEQ ID NO: 86) is the +401 base; ⑥ the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), is G; ⑦ the + 101th base, which is the polymorphic site of rs872375 (SEQ ID NO: 88), is G; ⑧ the +301 th base which is the polymorphic site of rs2302264 (SEQ ID NO: 89) is G; The +220 th base, the polymorphic site of rs1808279 (SEQ ID NO: 90), is A; And a haplotype marker for predicting interstitial gastric cancer susceptibility, wherein the + 218th base which is the polymorphic site of rs1790761 (SEQ ID NO: 91) is A. Scattered gastric cancer-related polynucleotide consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +417 th base, which is the polymorphic site of rs869736 (SEQ ID NO: 87), G or T, and the +417 th base Including, the gastric tissue or diagnostic sample for detecting gastric cancer, characterized in that for detecting the polymorphic site in the blood sample. The method of claim 10, ① Scattered gastric cancer-related poly of the polymorphic site of rs1476792 (SEQ ID NO: 82), wherein the +112 th base is T or C, and 20 to 100 consecutive nucleic acid molecules comprising the +112 th base or nucleic acid molecules complementary thereto Nucleotides; (2) Scattered gastric cancer-related polys composed of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules thereof, wherein the +401 th base, which is the polymorphic site of rs4930427 (SEQ ID NO: 83), is C or T and comprises the +401 th base; Nucleotides; ③ The sporadic gastric cancer-related poly of the polymorphic site of rs1790753 (SEQ ID NO: 84), wherein the +301 th base is G or A, and is composed of 20 to 100 consecutive nucleic acid molecules including the +301 th base or nucleic acid molecules complementary thereto. Nucleotides; (4) Scattered gastric cancer-related polys composed of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules thereof, wherein the +401 th base, which is the polymorphic site of rs1790752 (SEQ ID NO: 85), is C or T and comprises the +401 th base; Nucleotides; Scattered gastric cancer-related poly, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules containing the +401 th base, which is the polymorphic site of rs13859 (SEQ ID NO: 86), is C or T, and the +401 th base Nucleotides; ⑥ A polymorphic site of rs872375 (SEQ ID NO: 88), wherein the +101 base is G or A, and the interstitial gastric cancer-related poly consisting of 20 to 100 consecutive nucleic acid molecules comprising the +101 base or nucleic acid molecules complementary thereto Nucleotides; ⑦ interstitial gastric cancer-related poly, consisting of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +301 th base, which is the polymorphic site of rs2302264 (SEQ ID NO: 89), is G or A, and the +301 th base Nucleotides; ⑧ Scattered gastric cancer-related polys composed of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules including the +220 th base, which is the polymorphic site of rs1808279 (SEQ ID NO: 90), are A or G, and the +220 th base Nucleotides; And (9) Scattered gastric cancer-related polys composed of 20 to 100 consecutive nucleic acid molecules or complementary nucleic acid molecules comprising the +218 th base, which is the polymorphic site of rs1790761 (SEQ ID NO: 91), A or G, and the +218 th base Nucleotides; Further comprising at least one polynucleotide selected from the group consisting of, characterized in that for detecting the polymorphic site in the gastric tissue or blood samples, diagnostic reagents for the disseminated gastric cancer test. 1) extracting DNA from gastric tissue or blood sample isolated from the subject; 2) 20 to 100 bases of the polymorphic site of rs869736 (SEQ ID NO: 87), which are the polymorphic site of rs869736 (SEQ ID NO: 87), are G or T and include the + 417th base from the extracted DNA of step 1). Searching for polynucleotides consisting of consecutive nucleic acid molecules or nucleic acid molecules complementary thereto; And 3) comparing the search result of step 2) with the normal control, A method of searching for a polymorphic site to provide information on the risk of developing diffuse gastric cancer. The method of claim 12, further comprising, in step 2): Searching for a polymorphic site having a single base polymorphism and a correlation coeficient r-square of 0.95 or more, A method of searching for a polymorphic site to provide information on the risk of developing diffuse gastric cancer. The method of claim 12, further comprising, in step 2): Searching for a polymorphic site having a monobasic polymorphism and an associated disequilibrium coefficent of at least 0.95, A method of searching for a polymorphic site to provide information on the risk of developing diffuse gastric cancer.

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