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 OhnamiAkihiro 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

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300 Citations (Scopus)

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 × 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 r2 = 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 × 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.

Original languageEnglish
Pages (from-to)730-740
Number of pages11
JournalNature genetics
Volume40
Issue number6
DOIs
Publication statusPublished - 2008 Jun

ASJC Scopus subject areas

  • Genetics

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    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., ... Hirohashi, S. (2008). Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nature genetics, 40(6), 730-740. https://doi.org/10.1038/ng.152