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

  • Nat Genet. 2008 Jun;40(6):730-40. doi: 10.1038/ng.152.
Study Group of Millennium Genome Project for 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
PMID: 18488030 DOI: 10.1038/ng.152
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.