A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer patients.

Abstract

3025 Background: Radical surgery with subsequent adjuvant chemotherapy was effective treatment for early-stage gastric cancer (GC) patients. Unfortunately, after optimal multimodality therapy, up to 30% to 40% of patients undergoing resection will relapse within 5 years. There are no validated prognostic and predictive biomarkers for GC patients who receive adjuvant chemotherapy, and current patient selection is based mainly on postoperative pathological staging. Defective mismatch repair (MMR) or microsatellite instability (MSI) may affect GC outcome. Polymorphisms of MMR genes with a low-penetrant effect can cause heterogeneous MMR capability among individuals. It is not known about the impact of these polymorphisms on GC outcome. Methods: The polymorphisms rs1800734 in MLH1, rs2303428 and rs3732183 in MSH2, rs735943 in EXO1, and rs11797 in TREX1 were selected and analyzed in independent discovery and validation sets that included 167 and 593 patients, respectively. MSI was determined. Results: In the discovery set, both the rs2303428 TC+CC and the rs11797 GA+AA genotypes significantly correlated with poor overall survival (OS; P < 0.05). In the validation set, we confirmed the prognostic association for the rs2303428 TC+CC genotype (P = 0.036) but not for the rs11797 GA+AA genotype (P = 0.737). Furthermore, the prognostic role of the rs2303428 TC+CC genotype was observed in non-cardia (P = 0.005) but not in cardia GC (P = 0.934). The multivariate model showed that the rs2303428 TC+CC genotype was an independent predictor for OS in non-cardia patients (HR = 1.54; 95% CI: 1.02-2.32; P = 0.040). Moreover, fluoropyrimidines-based adjuvant chemotherapy significantly improved OS (HR = 0.29; 95% CI: 0.15-0.58; P < 0.001) for non-cardia patients with the rs2303428 TC+CC genotype but not for those with the rs2303428 TT genotype. The rs2303428 genotypes were not associated with MSI frequency. Conclusions: The rs2303428 TC+CC genotype may predict prognosis and adjuvant chemotherapy benefit in non-cardia GC patients independent of MSI. To our knowledge, our study is the first to report the prognostic and predictive roles of MMR genotype in GC. Although prospective validation is necessary, our findings have the potential to improve patient selection for adjuvant chemotherapy and spare large numbers of GC patients’ unnecessary therapy.