A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer.

Abstract

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 × 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 × 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.

• Authors: Norihisa Saeki, Akira Saito, Il Ju Choi, Keitaro Matsuo, Sumiko Ohnami, Hirohiko Totsuka, Suenori Chiku, Aya Kuchiba, Yeon-Su Lee, Kyong-Ah Yoon, Myeong-Cherl Kook, Sook Ryun Park, Young-Woo Kim, Hideo Tanaka, Kazuo Tajima, Hiroshi Hirose, Fumihiko Tanioka, Yoshihiro Matsuno, Haruhiko Sugimura, Shunji Kato, Tsuneya Nakamura, Tomohiro Nishina, Wataru Yasui, Kazuhiko Aoyagi, Hiroki Sasaki, Kazuyoshi Yanagihara, Hitoshi Katai, Tadakazu Shimoda, Teruhiko Yoshida, Yusuke Nakamura, Setsuo Hirohashi, Hiromi Sakamoto
• Journal: Gastroenterology (Gastroenterology) Vol. 140 Issue 3 Pg. 892-902 (Mar 2011) ISSN: 1528-0012 [Electronic] United States
• PMID: 21070779 (Publication Type: Journal Article, Meta-Analysis, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• MUC1 protein, human
• Mucin-1

Topics

• Asian People (genetics)
• Case-Control Studies
• Cell Line, Tumor
• Chromosomes, Human, Pair 1
• Exons
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Haplotypes
• Humans
• Japan (epidemiology)
• Linkage Disequilibrium
• Logistic Models
• Male
• Middle Aged
• Mucin-1 (genetics, metabolism)
• Odds Ratio
• Phenotype
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Republic of Korea (epidemiology)
• Risk Assessment
• Risk Factors
• Stomach Neoplasms (ethnology, genetics, pathology)
• Transfection