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

      Nature genetics

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

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          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.

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