Article abstract

Nature Genetics 40, 730 - 740 (2008)
Published online: 18 May 2008 | doi:10.1038/ng.152

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

The Study Group of Millennium Genome Project for Cancer

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- 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 times 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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  1. Genetics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  2. Department of Health Policy and Management, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
  3. Department of Surgical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  4. Pathology of Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  5. First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu-shi, Shizuoka 431-3192, Japan.
  6. Iwata City Hospital, 512-3 Ohkubo, Iwata-shi, Shizuoka 438-8550, Japan.
  7. Department of Surgery, Nippon Medical School Hospital, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
  8. Department of Endoscopy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
  9. Department of Internal Medicine, Shikoku Cancer Center, 160 Kou, Minamiumemoto-cho, Matsuyama-shi, Ehime 791-0280, Japan.
  10. Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
  11. Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
  12. SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
  13. Bioinfomatics Group, Research and Development Center, Solution Division 4, Hitachi Government and Public Corporation System Engineering Ltd., 2-4-18 Toyo, Koto-ku, Tokyo 135-8633, Japan.
  14. Bio-IT Business Promotion Center, Solution Development Laboratories, NEC Corporation, NEC, 5-7-1 Shiba, Minato-ku, Tokyo 108-8001, Japan.
  15. Statistical Genetics Analysis Division, StaGen Co., Ltd., Kuramae Orashion Bldg. 9F, 4-31-10 Kuramae Taito-ku, Tokyo 111-0051, Japan.
  16. Mitsui Knowledge Industry Co., Ltd., Hitotsubashi SI bldg., 3-26 Kandanishiki-cho, Chiyoda-ku, Tokyo 101-0054, Japan.
  17. Science Solutions Division, Mizuho Information and Research Institute, Inc., 2-3 Kanda-nishiki-cho, Chiyoda-ku, Tokyo 101-8443, Japan.
  18. Central RI Laboratory, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  19. Central Animal Laboratory, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  20. Research Institute and Hospital, National Cancer Center, 809 Madu 1-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do, 411-764, Korea.
  21. Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
  22. National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  23. Present address: Division of Gastroenterology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.
  24. These authors contributed equally to this work.

Correspondence to: e-mail: tyoshida@ncc.go.jp



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