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

Nature Genetics volume 40, pages 730–740 (2008)Cite this article

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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References

  1. Crew, K.D. & Neugut, A.I. Epidemiology of gastric cancer. World J. Gastroenterol. 12, 354–362 (2006).

    Article  Google Scholar 

  2. Ushijima, T. & Sasako, M. Focus on gastric cancer. Cancer Cell 5, 121–125 (2004).

    Article  CAS  Google Scholar 

  3. Lauren, P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand. 64, 31–49 (1965).

    Article  CAS  Google Scholar 

  4. Hohenberger, P. & Gretschel, S. Gastric cancer. Lancet 362, 305–315 (2003).

    Article  Google Scholar 

  5. Saito, A., Shimoda, T., Nakanishi, Y., Ochiai, A. & Toda, G. Histologic heterogeneity and mucin phenotypic expression in early gastric cancer. Pathol. Int. 51, 165–171 (2001).

    Article  CAS  Google Scholar 

  6. Machado, J.C. et al. E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas. Lab. Invest. 79, 459–465 (1999).

    CAS  PubMed  Google Scholar 

  7. Schier, S. & Wright, N.A. Stem cell relationships and the origin of gastrointestinal cancer. Oncology 69 (Suppl. 1), 9–13 (2005).

    Article  Google Scholar 

  8. Rosai, J. in Rosai and Ackerman's Surgical Pathology, Ch. 11, Gastrointestinal tract—stomach 648–711 (Mosby, Edinburgh, 2004).

    Google Scholar 

  9. Japanese Gastric Cancer Association Registration Committee. Gastric cancer treated in 1991 in Japan: data analysis of nationwide registry. Gastric Cancer 9, 51–66 (2006).

  10. Yokota, T. et al. Borrmann's type IV gastric cancer: clinicopathologic analysis. Can. J. Surg. 42, 371–376 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Henson, D.E., Dittus, C., Younes, M., Nguyen, H. & Albores-Saavedra, J. Differential trend in the intestinal and diffuse types of gastric carcinoma in United States, 1973–2000 – increase in the signet ring cell type. Arch. Pathol. Lab. Med. 128, 765–770 (2004).

    PubMed  Google Scholar 

  12. Shinmura, K. et al. Familial gastric cancer: clinicopathological characteristics, RER phenotype and germline p53 and E-cadherin mutations. Carcinogenesis 20, 1127–1131 (1999).

    Article  CAS  Google Scholar 

  13. Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer: analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343, 78–85 (2000).

    Article  CAS  Google Scholar 

  14. Correa, P. & Shiao, Y.-H. Phenotypic and genotypic events in gastric carcinogenesis. Cancer Res. 54 (7 Suppl.), 1941s–1943s (1994).

    CAS  PubMed  Google Scholar 

  15. González, C.A., Sala, N. & Capellá, G. Genetic susceptibility and gastric cancer risk. Int. J. Cancer 100, 249–260 (2002).

    Article  Google Scholar 

  16. Hirakawa, M. et al. JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res. 30, 158–162 (2002).

    Article  CAS  Google Scholar 

  17. Haga, H., Yamada, R., Nakamura, Y. & Tanaka, T. Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190,562 genetic variations in the human genome. J. Hum. Genet. 47, 605–610 (2002).

    Article  CAS  Google Scholar 

  18. Yoshida, T. & Yoshimura, K. Outline of disease gene hunting approaches in the Millennium Genome Project of Japan. Proc. Jpn. Acad. 79, 34–50 (2003).

    Article  Google Scholar 

  19. Kato, N. et al. High-density association study and nomination of susceptibility genes for hypertension in the Japanese National Project. Hum. Mol. Genet. 17, 617–627 (2008).

    Article  CAS  Google Scholar 

  20. Reiter, R.E. et al. Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc. Natl. Acad. Sci. USA 95, 1735–1740 (1998).

    Article  CAS  Google Scholar 

  21. Gu, Z. et al. Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer. Oncogene 19, 1288–1296 (2000).

    Article  CAS  Google Scholar 

  22. Bahrenberg, G., Brauers, A., Joost, H.-G. & Jakse, G. Reduced expression of PSCA, a member of the LY-6 family of cell surface antigen, in bladder, esophagus, and stomach tumors. Biochem. Biophys. Res. Commun. 275, 783–788 (2000).

    Article  CAS  Google Scholar 

  23. Sato, Y. et al. Designing a multistage, SNP-based, genome screen for common diseases. J. Hum. Genet. 49, 669–676 (2004).

    Article  CAS  Google Scholar 

  24. Karam, S. & Leblond, C.P. Origin and migratory pathways of the eleven epithelial cell types present in the body of the mouse stomach. Microsc. Res. Tech. 31, 193–214 (1995).

    Article  CAS  Google Scholar 

  25. Karam, S.M., Straiton, T., Hassen, W.M. & Leblond, C.P. Defining epithelial cell progenitors in the human oxyntic mucosa. Stem Cells 21, 322–336 (2003).

    Article  Google Scholar 

  26. Fukaya, M. et al. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Gastroenterology 131, 14–29 (2006).

    Article  CAS  Google Scholar 

  27. Saffran, D.C. et al. Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts. Proc. Natl. Acad. Sci. USA 98, 2658–2663 (2001).

    Article  CAS  Google Scholar 

  28. Gu, Z., Yamashiro, J., Kono, E. & Reiter, R.E. Anti-prostate stem cell antigen monoclonal antibody 1G8 induces cell death in vitro and inhibits tumor growth in vivo via a Fc-independent mechanism. Cancer Res. 65, 9495–9500 (2005).

    Article  CAS  Google Scholar 

  29. Wang, G.-Y., Lu, C.-Q., Zhang, R.-M., Hu, X.-H. & Luo, Z.W. The E-cadherin gene polymorphism -160C/A and cancer risk: A HuGE review and meta-analysis of 26 case-control studies. Am. J. Epidemiol. 167, 7–14 (2008).

    Article  Google Scholar 

  30. Humar, B. et al. Association of CDH1 haplotypes with susceptibility to sporadic diffuse gastric cancer. Oncogene 21, 8192–8195 (2002).

    Article  CAS  Google Scholar 

  31. Pharoah, P.D. et al. CDH1 c-160a promotor polymorphism is not associated with risk of stomach cancer. Int. J. Cancer 101, 196–197 (2002).

    Article  CAS  Google Scholar 

  32. Smith, M.G., Hold, G.L., Tahara, E. & El-Omar, E.M. Cellular and molecular aspects of gastric cancer. World J. Gastroenterol. 12, 2979–2990 (2006).

    Article  CAS  Google Scholar 

  33. Sasazuki, S. et al. Effect of Helicobacter pylori infection combined with CagA and pepsinogen status on gastric cancer development among Japanese men and women: a nested case-control study. Cancer Epidemiol. Biomarkers Prev. 15, 1341–1347 (2006).

    Article  CAS  Google Scholar 

  34. Kamangar, F., Cheng, C., Abnet, C.C. & Rabkin, C.S. Interleukin-1B polymorphisms and gastric cancer risk-a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 15, 1920–1928 (2006).

    Article  CAS  Google Scholar 

  35. Tran, C.P., Lin, C., Yamashiro, J. & Reiter, R.E. Prostate stem cell antigen is a marker of late intermediate prostate epithelial cells. Mol. Cancer Res. 1, 113–121 (2002).

    CAS  PubMed  Google Scholar 

  36. Sharom, F.J. & Radeva, G. GPI-anchored cleavage in the regulation of transmembrane signals. in Subcellular Biochemistry, Volume 37: Membrane Dynamics and Domains (ed. Quinn, P.J.) 285–315 (Kluwer Academic/Plenum Publishers, New York, 2004).

    Chapter  Google Scholar 

  37. De Nooij-van Dalen, A.G. et al. Characterization of the human LY-6 antigens, the newly annotated member LY-6K included, as molecular markers for head-and-neck squamous cell carcinoma. Int. J. Cancer 103, 768–774 (2003).

    Article  Google Scholar 

  38. Pharoah, P.D. et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat. Genet. 31, 33–36 (2002).

    Article  CAS  Google Scholar 

  39. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma. - 2nd English edition Gastric Cancer 1, 10–24 (1998).

  40. Fenoglio-Preiser, C. et al. Gastric carcinoma. in WHO Classification of Tumours: Tumours of the Digestive System (eds. Hamilton, S.R. & Aaltonen, L.A.) 39–52 (IARC Press, Lyon, 2000).

  41. Noguchi, M., Furuya, S., Takeuchi, T. & Hirohashi, S. Modified formalin and methanol fixation methods for molecular biological and morphological analyses. Pathol. Int. 47, 685–691 (1997).

    Article  CAS  Google Scholar 

  42. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    Article  CAS  Google Scholar 

  43. Hirschhorn, J.N. & Daly, M.J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108 (2005).

    Article  CAS  Google Scholar 

  44. Epstein, M.P. & Satten, G.A. Inference on haplotype effects in case-control studies using unphased genotype data. Am. J. Hum. Genet. 73, 1316–1329 (2003).

    Article  CAS  Google Scholar 

  45. Falush, D., Stephens, M. & Pritchard, J.K. Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164, 1567–1587 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bacanu, S.-A., Devlin, B. & Roeder, K. The power of genomic control. Am. J. Hum. Genet. 66, 1933–1944 (2000).

    Article  CAS  Google Scholar 

  47. Zhu, X., Zhang, S., Zhao, H. & Cooper, R.S. Association mapping, using a mixture model for complex traits. Genet. Epidemiol. 23, 181–196 (2002).

    Article  Google Scholar 

  48. Nei, M. Molecular Evolutionary Genetics (Columbia University Press, New York, 1987).

  49. Saeki, N. et al. GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-beta-dependent apoptotic signalling. Oncogene 26, 6488–6498 (2007).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Ichinosuke Hyodo

    Present address: Present address: Division of Gastroenterology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.,

  2. Hiromi Sakamoto, Kimio Yoshimura and Norihisa Saeki: These authors contributed equally to this work.

Authors and Affiliations

  1. Genetics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hiromi Sakamoto, Kimio Yoshimura, Norihisa Saeki, Sumiko Ohnami, Yasunori Sato, Kazuhiko Aoyagi, Hiroki Sasaki & Teruhiko Yoshida

  2. Department of Health Policy and Management, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Kimio Yoshimura

  3. Department of Surgical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hitoshi Katai, Daizo Saito & Emi Toshiro

  4. Pathology of Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Tadakazu Shimoda & Yoshihiro Matsuno

  5. First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu-shi, Shizuoka, 431-3192, Japan

    Haruhiko Sugimura

  6. Iwata City Hospital, 512-3 Ohkubo, Iwata-shi, Shizuoka, 438-8550, Japan

    Fumihiko Tanioka

  7. Department of Surgery, Nippon Medical School Hospital, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan

    Shunji Kato, Norio Matsukura & Noriko Matsuda

  8. Department of Endoscopy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

    Tsuneya Nakamura

  9. Department of Internal Medicine, Shikoku Cancer Center, 160 Kou, Minamiumemoto-cho, Matsuyama-shi, Ehime, 791-0280, Japan

    Ichinosuke Hyodo & Tomohiro Nishina

  10. Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Wataru Yasui

  11. Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Hiroshi Hirose & Matsuhiko Hayashi

  12. SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    Akihiro Sekine & Yusuke Nakamura

  13. Solution Division 4, Bioinfomatics Group, Research and Development Center, Hitachi Government and Public Corporation System Engineering Ltd., 2-4-18 Toyo, Koto-ku, Tokyo, 135-8633, Japan

    Hirohiko Totsuka

  14. Bio-IT Business Promotion Center, Solution Development Laboratories, NEC Corporation, NEC, 5-7-1 Shiba, Minato-ku, Tokyo, 108-8001, Japan

    Masataka Ando

  15. Statistical Genetics Analysis Division, StaGen Co., Ltd., Kuramae Orashion Bldg. 9F, 4-31-10 Kuramae Taito-ku, Tokyo, 111-0051, Japan

    Ryo Takemura

  16. Mitsui Knowledge Industry Co., Ltd., Hitotsubashi SI bldg., 3-26 Kandanishiki-cho, Chiyoda-ku, Tokyo, 101-0054, Japan

    Yoriko Takahashi, Minoru Ohdaira, Kenichi Aoki & Izumi Honmyo

  17. Science Solutions Division, Mizuho Information and Research Institute, Inc., 2-3 Kanda-nishiki-cho, Chiyoda-ku, Tokyo, 101-8443, Japan

    Suenori Chiku

  18. Central RI Laboratory, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Shumpei Ohnami

  19. Central Animal Laboratory, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Kazuyoshi Yanagihara

  20. Research Institute and Hospital, National Cancer Center, 809 Madu 1-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do, 411-764, Korea

    Kyong-Ah Yoon, Myeong-Cherl Kook, Yeon-Su Lee, Sook Ryun Park, Chan Gyoo Kim & Il Ju Choi

  21. Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yusuke Nakamura

  22. National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Setsuo Hirohashi

Consortia

The 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

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.

Corresponding author

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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