Cancer Res Treat.  2019 Apr;51(2):748-757. 10.4143/crt.2018.162.

Genome-Wide Association of Genetic Variation in the PSCA Gene with Gastric Cancer Susceptibility in a Korean Population

• Park B
• Yang S
• Lee J
• Woo HD
• Choi IJ
• Kim YW
• Ryu KW
• Kim YI
• Kim J

• KMID: 2464420
• DOI: http://doi.org/10.4143/crt.2018.162

Abstract

PURPOSE
Half of the world's gastric cancer cases and the highest gastric cancer mortality rates are observed in Eastern Asia. Although several genome-wide association studies (GWASs) have revealed susceptibility genes associated with gastric cancer, no GWASs have been conducted in the Korean population, which has the highest incidence of gastric cancer.
MATERIALS AND METHODS
We performed genome scanning of 450 gastric cancer cases and 1,134 controls via Affymetrix Axiom Exome 319 arrays, followed by replication of 803 gastric cancer cases and 3,693 healthy controls.
RESULTS
We showed that the rs2976394 in the prostate stem cell antigen (PSCA) gene is a gastriccancer-susceptibility gene in a Korean population, with genome-wide significance and an odds ratio (OR) of 0.70 (95% confidence interval [CI], 0.64 to 0.77). A strong linkage disequilibrium with rs2294008 was also found, indicating an association with susceptibility. Individuals with the CC genotype of the PSCA gene showed an approximately 2-fold lower risk of gastric cancer compared to those with the TT genotype (OR, 0.47; 95% CI, 0.39 to 0.57). The effect of the PSCA gene on gastric cancer was more prominent in the female population and for diffuse type gastric cancer.
CONCLUSION
Our result confirmed that the PSCA gene may be the most important susceptibility gene for gastric cancer risk in a Korean population.

Keyword

Stomach neoplasms; Genome-wide association study; Prostate stem cell antigen gene

MeSH Terms

Exome
Far East
Female
Genetic Variation*
Genome
Genome-Wide Association Study
Genotype
Humans
Incidence
Linkage Disequilibrium
Mortality
Odds Ratio
Prostate
Stem Cells
Stomach Neoplasms*

Figure

• 

  Fig. 1. Linkage disequilibrium plot and regional plot of rs2294008 in study subjects in the discovery phase. (A) Linkage disequilibrium plot. (B) Regional plot.

Reference

References

1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, et al. The Global Burden of Cancer 2013. JAMA Oncol. 2015; 1:505–27.

2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010; 127:2893–917.

3. Compare D, Rocco A, Nardone G. Risk factors in gastric cancer. Eur Rev Med Pharmacol Sci. 2010; 14:302–8.

4. Palli D. Epidemiology of gastric cancer: an evaluation of available evidence. J Gastroenterol. 2000; 35 Suppl 12:84–9.

5. Singh K, Ghoshal UC. Causal role of Helicobacter pylori infection in gastric cancer: an Asian enigma. World J Gastroenterol. 2006; 12:1346–51.

6. Study Group of Millennium Genome Project for Cancer, Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T, et al. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat Genet. 2008; 40:730–40.

7. 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.

8. 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.

9. Jin G, Ma H, Wu C, Dai J, Zhang R, Shi Y, et al. Genetic variants at 6p21.1 and 7p15.3 are associated with risk of multiple cancers in Han Chinese. Am J Hum Genet. 2012; 91:928–34.

10. Hu N, Wang Z, Song X, Wei L, Kim BS, Freedman ND, et al. Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and noncardia tumours. Gut. 2016; 65:1611–8.

11. Helgason H, Rafnar T, Olafsdottir HS, Jonasson JG, Sigurdsson A, Stacey SN, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet. 2015; 47:906–10.

12. Leung WK, Wu MS, Kakugawa Y, Kim JJ, Yeoh KG, Goh KL, et al. Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol. 2008; 9:279–87.

13. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81:559–75.

14. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient metaanalysis of genomewide association scans. Bioinformatics. 2010; 26:2190–1.

15. Sharom FJ, Radeva G. GPI-anchored protein cleavage in the regulation of transmembrane signals. Subcell Biochem. 2004; 37:285–315.

16. 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.

17. Grubbs EG, Abdel-Wahab Z, Tyler DS, Pruitt SK. Utilizing quantitative polymerase chain reaction to evaluate prostate stem cell antigen as a tumor marker in pancreatic cancer. Ann Surg Oncol. 2006; 13:1645–54.

18. 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.

19. Shi D, Wang S, Gu D, Wu D, Wang M, Chu H, et al. The PSCA polymorphisms derived from genome-wide association study are associated with risk of gastric cancer: a meta-analysis. J Cancer Res Clin Oncol. 2012; 138:1339–45.

20. Wang T, Zhang L, Li H, Wang B, Chen K. Prostate stem cell antigen polymorphisms and susceptibility to gastric cancer: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2012; 21:843–50.

21. Garcia-Gonzalez MA, Bujanda L, Quintero E, Santolaria S, Benito R, Strunk M, et al. Association of PSCA rs2294008 gene variants with poor prognosis and increased susceptibility to gastric cancer and decreased risk of duodenal ulcer disease. Int J Cancer. 2015; 137:1362–73.

22. Song HR, Kim HN, Piao JM, Kweon SS, Choi JS, Bae WK, et al. Association of a common genetic variant in prostate stemcell antigen with gastric cancer susceptibility in a Korean population. Mol Carcinog. 2011; 50:871–5.

23. Lim SH, Kwon JW, Kim N, Kim GH, Kang JM, Park MJ, et al. Prevalence and risk factors of Helicobacter pylori infection in Korea: nationwide multicenter study over 13 years. BMC Gastroenterol. 2013; 13:104.

24. Wang M, Zhang R, He J, Qiu L, Li J, Wang Y, et al. Potentially functional variants of PLCE1 identified by GWASs contribute to gastric adenocarcinoma susceptibility in an eastern Chinese population. PLoS One. 2012; 7:e31932.

25. Gan-Or Z, Bar-Shira A, Gurevich T, Giladi N, Orr-Urtreger A. Homozygosity for the MTX1 c.184T>A (p.S63T) alteration modifies the age of onset in GBA-associated Parkinson's disease. Neurogenetics. 2011; 12:325–32.

26. Mocellin S, Verdi D, Pooley KA, Nitti D. Genetic variation and gastric cancer risk: a field synopsis and meta-analysis. Gut. 2015; 64:1209–19.

27. Kim YD, Yim DH, Eom SY, Moon SI, Yun HY, Song YJ, et al. Risk of gastric cancer is associated with PRKAA1 gene polymorphisms in Koreans. World J Gastroenterol. 2014; 20:8592–8.

28. Song HR, Kim HN, Kweon SS, Choi JS, Shim HJ, Cho SH, et al. Common genetic variants at 1q22 and 10q23 and gastric cancer susceptibility in a Korean population. Tumour Biol. 2014; 35:3133–7.

29. Hwang JY, Kim DH, Ji YI, Go MJ, Heo L, Kim YJ, 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.