Tumor Biology

, Volume 35, Issue 3, pp 2167–2174 | Cite as

Quantitative assessment of the influence of prostate stem cell antigen polymorphisms on gastric cancer risk

  • Xixi Gu
  • Wen Zhang
  • Lili Xu
  • Dingfang Cai
Research Article


Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored 123-amino acid protein related to the cell proliferation inhibition and/or cell death induction activity which has attracted considerable attention as a candidate gene for gastric cancer (GC) since it was first identified through genome-wide association approach. Since then, the relationship between PSCA polymorphisms (rs2294008, rs2976392) and GC has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 16 studies involving a total of 18,820 cases and 35,756 controls for the two widely studied polymorphisms of PSCA on genetic susceptibility for GC. Overall, the summary odds ratio for GC was 1.46 (95 % CI 1.30–1.69, P < 10−5) and 1.49 (95 % CI 1.22–1.82, P < 10−4) for PSCA rs2294008 and rs2976392 polymorphisms, respectively. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and GC risk. When stratifying for ethnicity, significantly increased risks were found for rs2294008 and rs2976392 polymorphism among East Asians in all genetic models, while no significant associations were observed for the rs2294008 polymorphism in Caucasians. In the stratified analyses according to histological type, and source of controls, evidence of gene-disease association was still obtained. In addition, our data indicate that rs2294008 of PSCA is involved in GC susceptibility and confer its effect primarily in noncardia tumors (OR = 1.30, 95 % CI 1.12–1.53, P < 10−4). Our findings demonstrated that rs2294008 and rs2976392 polymorphism of PSCA is a risk-conferring factor associated with increased GC susceptibility, especially in East Asians.


Gastric cancer PSCA Polymorphism Meta-analysis 


Conflicts of interest


Supplementary material

13277_2013_1287_MOESM1_ESM.doc (164 kb)
ESM 1 (DOC 164 kb)


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRefGoogle Scholar
  2. 2.
    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. 1965;64:31–49.PubMedGoogle Scholar
  3. 3.
    Cuello C, López J, Correa P, Murray J, Zarama G, Gordillo G. Histopathology of gastric dysplasias: correlations with gastric juice chemistry. Am J Surg Pathol. 1979;3:491–500.PubMedCrossRefGoogle Scholar
  4. 4.
    Correa P, Schneider BG. Etiology of gastric cancer: what is new? Cancer Epidemiol Biomarkers Prev. 2005;14:1865–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Zagari RM, Bazzoli F. Gastric cancer: who is at risk? Dig Dis. 2004;22:302–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Roberts-Thomson IC, Butler WJ. Polymorphism and gastric cancer. J Gastroenterol Hepatol. 2005;20:793–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Gonzalez CA, Sala N, Capella G. Genetic susceptibility and gastric cancer risk. Int J Cancer. 2002;100:249–60.PubMedCrossRefGoogle Scholar
  8. 8.
    Agudo A, Sala N, Pera G, Capellá G, Berenguer A, García N, et al. Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev. 2006;15:2427–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Gao L, Nieters A, Brenner H. Cell proliferation-related genetic polymorphisms and gastric cancer risk: systematic review and meta-analysis. Eur J Hum Genet. 2009;17:1658–67.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Crusius JB, Canzian F, Capellá G, Peña AS, Pera G, Sala N, et al. Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST). Ann Oncol. 2008;19:1894–902.PubMedCrossRefGoogle Scholar
  11. 11.
    Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T, Matsuno Y, et al. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat Genet. 2008;40:730–40.PubMedCrossRefGoogle Scholar
  12. 12.
    Shi Y, Hu Z, Wu C, Dai J, Li H, Dong J, et al. A genome-wide association study identifies new susceptibility loci for non-cardia gastric cancer at 3q13.31 and 5p13.1. Nat Genet. 2011;43:1215–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Reiter RE, Gu Z, Watabe T, Thomas G, Szigeti K, Davis E, et al. Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci U S A. 1998;95:1735–40.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Saeki N, Gu J, Yoshida T, Wu X. Prostate stem cell antigen: a Jekyll and Hyde molecule? Clin Cancer Res. 2010;16:3533–8.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Li DW, Collier DA, He L. Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hu Mol Genet. 2006;15:1995–2002.CrossRefGoogle Scholar
  16. 16.
    Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.PubMedGoogle Scholar
  17. 17.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.PubMedCrossRefGoogle Scholar
  18. 18.
    Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med. 1999;18:2693–708.PubMedCrossRefGoogle Scholar
  19. 19.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.PubMedCrossRefGoogle Scholar
  21. 21.
    Egger M, Davey Smith G, Schneider M. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Matsuo K, Tajima K, Suzuki T, Kawase T, Watanabe M, Shitara K, et al. Association of prostate stem cell antigen gene polymorphisms with the risk of stomach cancer in Japanese. Int J Cancer. 2009;125:1961–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Wu C, Wang G, Yang M, Huang L, Yu D, Tan W, et al. Two genetic variants in prostate stem cell antigen and gastric cancer susceptibility in a Chinese population. Mol Carcinog. 2009;48:1131–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Abnet CC, Freedman ND, Hu N, Wang Z, Yu K, Shu XO, et al. A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet. 2010;42:764–7.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Ou J, Li K, Ren H, Bai H, Zeng D, Zhang C. Association and haplotype analysis of prostate stem cell antigen with gastric cancer in Tibetans. DNA Cell Biol. 2010;29:319–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Lu Y, Chen J, Ding Y, Jin G, Wu J, Huang H, et al. Genetic variation of PSCA gene is associated with the risk of both diffuse- and intestinal-type gastric cancer in a Chinese population. Int J Cancer. 2010;127:2183–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Song HR, Kim HN, Piao JM, Kweon SS, Choi JS, Bae WK, et al. Association of a common genetic variant in prostate stem-cell antigen with gastric cancer susceptibility in a Korean population. Mol Carcinog. 2011;50:871–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Zeng Z, Wu X, Chen F, Yu J, Xue L, Hao Y, et al. Polymorphisms in prostate stem cell antigen gene rs2294008 increase gastric cancer risk in Chinese. Mol Carcinog. 2011;50:353–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Lochhead P, Frank B, Hold GL, Rabkin CS, Ng MT, Vaughan TL, et al. Genetic variation in the prostate stem cell antigen gene and upper gastrointestinal cancer in white individuals. Gastroenterology. 2011;140:435–41.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Sala N, Munoz X, Travier N, Agudo A, Duell EJ, Moreno V, et al. Prostate stem cell antigen gene is associated with diffuse and intestinal gastric cancer in Caucasians: results from the EPIC-EURGAST Study. Int J Cancer. 2012;130:2417–27.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhao JD, Geng PL, Zhao JH, Wang LJ, Ji FX, Li JZ, et al. Relationship between the rs2294008 polymorphism of the PSCA gene and susceptibility to gastric cancer in Tibetans. World Chin J Digestology. 2012;20:418–21.Google Scholar
  32. 32.
    Li F, Zhong MZ, Li JH, Liu W, Li B. Case–control study of single nucleotide polymorphisms of PSCA and MUC1 genes with gastric cancer in a Chinese. Asian Pac J Cancer Prev. 2012;13:2593–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Tanikawa C, Urabe Y, Matsuo K, Kubo M, Takahashi A, Ito H, et al. A genome-wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population. Nat Genet. 2012;44(430–4):S1–2.Google Scholar
  34. 34.
    Hwang JY, Kim DH, Ji YI, Jin Go M, Heo L, Jin Kim Y, et al. Recapitulation of previous genome-wide association studies with two distinct pathophysiological entities of gastric cancer in the Korean population. J Hum Genet. 2013;58:233–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Hirschhorn JN, Lohmueller K, Byrne E. A comprehensive review of genetic association studies. Genet Med. 2002;4:45–61.PubMedCrossRefGoogle Scholar
  36. 36.
    La Torre G, Chiaradia G, Gianfagna F, De Lauretis A, Boccia S, Mannocci A, et al. Smoking status and gastric cancer risk: an updated meta-analysis of case–control studies published in the past ten years. Tumori. 2009;95:13–22.PubMedGoogle Scholar
  37. 37.
    El-Omar EM, Chow WH, Rabkin CS. Gastric cancer and H. pylori: host genetics open the way. Gastroenterology. 2001;121:1002–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Gu Z, Thomas G, Yamashiro J, Shintaku IP, Dorey F, Raitano A, et al. Prostate stem cell antigen (PSCA) expression increases with high Gleason score, advanced stage and bone metastasis in prostate cancer. Oncogene. 2000;19:1288–96.PubMedCrossRefGoogle Scholar
  39. 39.
    Schoeman JH, De Vos V, Van Aswegen G. Distribution of endocrine cells in the gut of the impala. Ondersteport J Vet Res. 1998;65:31–5.Google Scholar
  40. 40.
    Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006;12:354–62.PubMedGoogle Scholar
  41. 41.
    Bahrenberg G, Brauers A, Joost HG, Jakse G. Reduced expression of PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors. Biochem Biophys Res Commun. 2000;275:783–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Argani P, Rosty C, Reiter RE, Wilentz RE, Murugesan SR, Leach SD, et al. Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. Cancer Res. 2001;61:4320–4.PubMedGoogle Scholar
  43. 43.
    de Nooij-van Dalen AG, van Dongen GA, Smeets SJ, Nieuwenhuis EJ, Stigter-van Walsum M, Snow GB, et al. Chracterization 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. 2003;103:768–74.PubMedCrossRefGoogle Scholar
  44. 44.
    Saffran DC, Raitano AB, Hubert RS, Witte ON, Reiter RE, Jakobovits A. Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts. Proc Natl Acad Sci U S A. 2001;98:2658–63.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Gu Z, Yamashiro J, Kono E, Reiter RE. 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. 2005;65:9495–500.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.Department of Traditional Chinese Medicine, Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China

Personalised recommendations