TY - JOUR
T1 - Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer
AU - Sakamoto, Hiromi
AU - Yoshimura, Kimio
AU - Saeki, Norihisa
AU - Katai, Hitoshi
AU - Shimoda, Tadakazu
AU - Matsuno, Yoshihiro
AU - Saito, Daizo
AU - Sugimura, Haruhiko
AU - Tanioka, Fumihiko
AU - Kato, Shunji
AU - Matsukura, Norio
AU - Matsuda, Noriko
AU - Nakamura, Tsuneya
AU - Hyodo, Ichinosuke
AU - Nishina, Tomohiro
AU - Yasui, Wataru
AU - Hirose, Hiroshi
AU - Hayashi, Matsuhiko
AU - Toshiro, Emi
AU - Ohnami, Sumiko
AU - Sekine, Akihiro
AU - Sato, Yasunori
AU - Totsuka, Hirohiko
AU - Ando, Masataka
AU - Takemura, Ryo
AU - Takahashi, Yoriko
AU - Ohdaira, Minoru
AU - Aoki, Kenichi
AU - Honmyo, Izumi
AU - Chiku, Suenori
AU - Aoyagi, Kazuhiko
AU - Sasaki, Hiroki
AU - Ohnami, Shumpei
AU - Yanagihara, Kazuyoshi
AU - Yoon, Kyong Ah
AU - Kook, Myeong Cherl
AU - Lee, Yeon Su
AU - Park, Sook Ryun
AU - Kim, Chan Gyoo
AU - Choi, Il Ju
AU - Yoshida, Teruhiko
AU - Nakamura, Yusuke
AU - Hirohashi, Setsuo
N1 - Funding Information:
This work was supported in Japan by the program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio) and by Health and Labour Sciences Research Grants by Ministry of Health, Labour and Welfare. The Korean part of the study was supported by grant 0710340 from the National Cancer Center, Korea. We thank the following people (listed in alphabetical order) for discussion and technical and statistical assistance: M. Asako, T. Chujo, C. Hamada, T. Hayashida, C. Hirama, F. Igarashi, T. Imai, E. Inoue, S. Kamakami, A. Katoh, O. Kawaguchi, C. Kina, N. Kurata, Y. Liu, G. Maeno, S. Mimaki, N. Mitsuhashi, N. Miyahara, A. Miyaoka, R. Nakajima, J. Nakata, Y. Odaka, T. Ogiwara, N. Ohsawa, E. Ohshima, M. Okada, M. Okuyama, Y. Sakashita, M. Sato, M. Seishi, T. Sobue, H. Suganami, E. Takemoto, T. Taniguchi, S. Uchida, T. Urushidate, M. Ushiama, S. Yabe, N. Yamaguchi, S. Yamamoto and I. Yoshimura.
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.152
DO - 10.1038/ng.152
M3 - Article
C2 - 18488030
AN - SCOPUS:44349178008
SN - 1061-4036
VL - 40
SP - 730
EP - 740
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -
