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

Author

Saeki N, Saito A, Choi IJ, Matsuo K, Ohnami S, Totsuka H, Chiku S, Kuchiba A, Lee YS, Yoon KA, Kook MC, Park SR, Kim YW, Tanaka H, Tajima K, Hirose H, Tanioka F, Matsuno Y, Sugimura H, Kato S, Nakamura T, Nishina T, Yasui W, Aoyagi K, Sasaki H, Yanagihara K, Katai H, Shimoda T, Yoshida T, Nakamura Y, Hirohashi S, and Sakamoto H

Subjects
Asian People genetics, Case-Control Studies, Cell Line, Tumor, Exons, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Japan epidemiology, Linkage Disequilibrium, Logistic Models, Male, Middle Aged, Mucin-1 metabolism, Odds Ratio, Phenotype, Promoter Regions, Genetic, Republic of Korea epidemiology, Risk Assessment, Risk Factors, Stomach Neoplasms ethnology, Stomach Neoplasms pathology, Transfection, Chromosomes, Human, Pair 1, Mucin-1 genetics, Polymorphism, Single Nucleotide, Stomach Neoplasms genetics
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., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Published
2011
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2. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer.

Author

Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T, Matsuno Y, Saito D, Sugimura H, Tanioka F, Kato S, Matsukura N, Matsuda N, Nakamura T, Hyodo I, Nishina T, Yasui W, Hirose H, Hayashi M, Toshiro E, Ohnami S, Sekine A, Sato Y, Totsuka H, Ando M, Takemura R, Takahashi Y, Ohdaira M, Aoki K, Honmyo I, Chiku S, Aoyagi K, Sasaki H, Ohnami S, Yanagihara K, Yoon KA, Kook MC, Lee YS, Park SR, Kim CG, Choi IJ, Yoshida T, Nakamura Y, and Hirohashi S

Subjects
Adenocarcinoma genetics, Adenocarcinoma pathology, Adenocarcinoma, Mucinous genetics, Adenocarcinoma, Mucinous pathology, Animals, Antigens, Neoplasm, CHO Cells, Carcinoma, Papillary genetics, Carcinoma, Papillary pathology, Carcinoma, Signet Ring Cell genetics, Carcinoma, Signet Ring Cell pathology, Case-Control Studies, Cell Proliferation, Cricetinae, Cricetulus, Epithelium, Exons genetics, GPI-Linked Proteins, Gene Frequency, Haplotypes genetics, Humans, Immunoenzyme Techniques, Intestinal Neoplasms, Japan, Korea, Linkage Disequilibrium, Membrane Glycoproteins metabolism, Mice, Neoplasm Proteins metabolism, Odds Ratio, Promoter Regions, Genetic, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Stomach Neoplasms pathology, Transcription, Genetic, Genetic Predisposition to Disease, Genetic Variation, Genome, Human genetics, Membrane Glycoproteins genetics, Neoplasm Proteins genetics, Polymorphism, Single Nucleotide genetics, Stomach Neoplasms genetics
Abstract

Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.

Published
2008
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