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

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.

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Figure 1: LD analyses of the SNPs in the genomic region around PSCA.
Figure 2: Expression of PSCA in the gastric epithelium.
Figure 3: Cell-growth inhibition activity of PSCA and the regulation of the PSCA promoter activity by SNP in the upstream region of the gene.

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Acknowledgements

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.

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Contributions

Principal investigators: H. Sakamoto, K. Yoshimura and N.S. Gastric cancer project planning and design: H. Sakamoto, K. Yoshimura, T.Y., H.K. and T.S. Ascertainment of subjects for genetic analyses: H.K., T.S., Y.M., D.S., H. Sugimura, F.T., S.K., N. Matsukura, N. Matsuda, T. Nakamura, I. Hyodo, T. Nishina, W.Y., H.H., M.H., E.T. and S.H. Genetic analyses: H. Sakamoto, Sumiko Ohnami, A.S. and Y.N. Statistical analyses and database: K. Yoshimura, Y.S., H.T., M.A., R.T., Y.T., M.O., K. Aoki, I. Honmyo and S.C. Functional analyses: N.S., K. Aoyagi, H. Sasaki, Sumiko Ohnami, Shunpei Ohnami, K. Yanagihara and H. Sakamoto. National Cancer Center, Korea: K.-A.Y., M.-C.K., Y.-S.L., S.R.P., C.G.K. and I.J.C. Millennium Genome Project Cancer Subteam Leader: T.Y. Millennium Genome Project Human Genome Variation Team Leader: Y.N. Millennium Genome Project Disease Gene Team Leader: S.H.

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Correspondence to Teruhiko Yoshida.

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The Study Group of Millennium Genome Project for Cancer. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat Genet 40, 730–740 (2008). https://doi.org/10.1038/ng.152

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