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Nature Genetics 40, 730–740 (1 June 2008) | doi:10.1038/ng.152

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

Hiromi Sakamoto , Kimio Yoshimura , Norihisa Saeki , Hitoshi Katai , Tadakazu Shimoda , Yoshihiro Matsuno , Daizo Saito , Haruhiko Sugimura , Fumihiko Tanioka , Shunji Kato , Norio Matsukura , Noriko Matsuda , Tsuneya Nakamura , Ichinosuke Hyodo , Tomohiro Nishina , Wataru Yasui , Hiroshi Hirose , Matsuhiko Hayashi , Emi Toshiro , Sumiko Ohnami , Akihiro Sekine , Yasunori Sato , Hirohiko Totsuka , Masataka Ando , Ryo Takemura , Yoriko Takahashi , Minoru Ohdaira , Kenichi Aoki , Izumi Honmyo , Suenori Chiku , Kazuhiko Aoyagi , Hiroki Sasaki , Shumpei Ohnami , Kazuyoshi Yanagihara , Kyong-Ah Yoon , Myeong-Cherl Kook , Yeon-Su Lee , Sook Ryun Park , Chan Gyoo Kim , Il Ju Choi , Teruhiko Yoshida , Yusuke Nakamura & Setsuo Hirohashi

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 |[times]| 10|[minus]|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 r2 = 0.995, D|[prime]| = 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 |[times]| 10|[minus]|11). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.