A Functional Single Nucleotide Polymorphism in Mucin 1, at Chromosome 1q22, Determines Susceptibility to Diffuse-Type Gastric Cancer

被引：101

作者：

Saeki, Norihisa

Saito, Akira ^{[2
]}

Choi, Il Ju ^{[3
]}

Matsuo, Keitaro ^{[4
]}

Ohnami, Sumiko

Totsuka, Hirohiko ^{[5
]}

Chiku, Suenori ^{[6
]}

Kuchiba, Aya

Lee, Yeon-Su ^{[3
]}

Yoon, Kyong-Ah ^{[3
]}

Kook, Myeong-Cherl ^{[3
]}

Park, Sook Ryun ^{[3
]}

Kim, Young-Woo ^{[3
]}

Tanaka, Hideo ^{[4
]}

Tajima, Kazuo ^{[4
]}

Hirose, Hiroshi ^{[7
]}

Tanioka, Fumihiko ^{[8
]}

Matsuno, Yoshihiro ^{[9
]}

Sugimura, Haruhiko ^{[10
]}

Kato, Shunji ^{[11
]}

Nakamura, Tsuneya ^{[12
]}

Nishina, Tomohiro ^{[13
]}

Yasui, Wataru ^{[14
]}

Aoyagi, Kazuhiko

Sasaki, Hiroki

Yanagihara, Kazuyoshi ^{[15
]}

Katai, Hitoshi ^{[16
]}

Shimoda, Tadakazu ^{[17
]}

Yoshida, Teruhiko ^{[1
]}

Nakamura, Yusuke ^{[18
]}

Hirohashi, Setsuo

Sakamoto, Hiromi

机构：

[1] Natl Canc Ctr, Res Inst, Div Genet, Chuo Ku, Tokyo 1040045, Japan

[2] StaGen Co Ltd, Stat Genet Anal Div, Tokyo, Japan

[3] Natl Canc Ctr, Res Inst Hosp, Goyang 411769, Gyeonggi, South Korea

[4] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan

[5] Hitachi Govt & Public Corp Syst Engn Ltd, Solut Div 4, Bioinfomat Grp, Ctr Res & Dev, Tokyo, Japan

[6] Mizuho Information & Res Inst Inc, Sci Solut Div, Tokyo, Japan

[7] Keio Univ, Sch Med, Dept Internal Med, Tokyo, Japan

[8] Iwata City Hosp, Shizuoka, Japan

[9] Hokkaido Univ Hosp, Dept Surg Pathol, Sapporo, Hokkaido 060, Japan

[10] Hamamatsu Univ Sch Med, Dept Pathol 1, Shizuoka, Japan

[11] Nippon Med Coll Hosp, Dept Surg, Tokyo, Japan

[12] Aichi Canc Ctr Hosp, Dept Endoscopy, Nagoya, Aichi 464, Japan

[13] Shikoku Canc Ctr, Dept Internal Med, Shikoku, Ehime, Japan

[14] Hiroshima Univ, Dept Mol Pathol, Grad Sch Biomed Sci, Hiroshima, Japan

[15] Yasuda Womens Univ, Dept Life Sci, Fac Pharm, Hiroshima, Japan

[16] Natl Canc Ctr, Dept Surg Oncol, Tokyo, Japan

[17] Natl Canc Ctr, Ctr Canc Control & Informat Serv, Tokyo 104, Japan

[18] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Tokyo, Japan

来源：

GASTROENTEROLOGY | 2011年 / 140卷 / 03期

关键词：

Stomach Cancer; Risk Genotype; Cancer Prevention; Genome-Wide Association Study; MUC1 GENE POLYMORPHISM; MOLECULAR-CLONING; GENOTYPE DATA; CARCINOMA; PROTEIN; EXPRESSION; PROGNOSIS; BLOCKS; MODEL; RISK;

D O I：

10.1053/j.gastro.2010.10.058

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & AIMS: Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated. METHODS: We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. RESULTS: A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 X 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 X 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). CONCLUSIONS: MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.

引用

页码：892 / 902

页数：11

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