Relevance of PSCA rs2294008 gene polymorphism on gastric cancer risk and prognosis

Abstract

Background & aim: The PSCA (prostate stem cell antigen) gene encodes a cell membrane glycoprotein involved in complex intracellular signaling pathways. A previous genome-wide association study (GWAS) reported the association between the PSCA rs2294008 gene polymorphism and gastric cancer (GC) risk, particularly of the diffuse histological type. However, studies evaluating the impact on the risk of the intestinal-type and GC prognosis show controversial results. The aim of our study was to assess the role of the PSCA rs2294008 gene polymorphism on GC risk and prognosis in a large case-control study in Spain. Method(s): Six hundred and thirty two unrelated Spanish Caucasians patients diagnosed with primary GC from May 2002 to December 2008 and 632 sex- and aged- (+/- 5 years) matched cancerfree healthy controls were included in the study. Genomic DNA from patients and controls was typed for the PSCA rs2294008 C.T variants by PCR-TaqMan assays. H. pylori infection and CagA/VacA antibody status were determined by western blot in patients and controls. Result(s): H. pylori infection with CagA strains (OR:2.12; 95% CI:1.7-2.76), smoking habit (OR:1.98; 95% CI:1.20-2.23) and positive family history of GC (OR:3.17; 95% CI:1.86- 4.29) were identified as independent risk factors for GC. In addition, the T allele of the PSCA rs2294008 polymorphism was associated specifically with increased risk of distal GC (TT+CT vs. CC; OR:1.12, 95% CI:1.03-1.43). Further stratification analyses indicated that the effect of PSCA rs2294008T on distal GC risk was restricted to H. pylori uninfected individuals (OR:1.39; 95% CI:1.05-1.85). This association was found in both intestinal (OR:1.21; 95% CI: 1.04-1.76) and diffuse (OR:1.48; 95% CI: 1.12-2.03) histological types. PSCA rs2294008 genotype frequencies in H. pylori positive distal GC patients were similar to those observed in H. pylori positive controls (T/T: 20.8% vs. 20.9%; T/C: 50.8% vs. 48.2%; C/C: 28.4% vs. 30.9%, respectively). Cox proportional hazards analyses demonstrated that advanced TNM stages (III and IV, HR, 3.23; 95% CI:2-5.22, and HR, 5.5; 95% CI: 3.51-8.63, respectively) and surgical treatment (HR: 0.44; 95%CI: 0.3-0.6) were related to the prognosis of the disease. No significant association between rs2294008 variants and GC survival was observed. However, when subgroup analysis by histological subtype was performed, an association between the rs2294008T variant and worse survival was found in the group of diffuse GC patients (TT+CT carrier median survival 326 vs. CC carrier median survival 599; HR:1.98, 95%CI:=1.22-3.22). Conclusion(s): Our data show that, in our population, the PSCA rs2294008 C.T gene polymorphism is associated with increased risk of distal GC in H. pylori-negative individuals, and with a worse prognosis of the disease in diffuse-type GC patients.