Prognostic role of thymidylate synthase (TS) gene polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy

Abstract

4044 Background: Previous studies suggest that TS expression in tumor tissue is related with both sensitivity to 5-FU-based chemotherapy and patients’outcome. TS gene has polymorphic sequences in its untranslated region (UTR) which are associated with TS expression. Aim of this study is to evaluate prognostic role of the TS polymorphisms in gastric cancer patients treated with surgery and 5-FU-based adjuvant chemotherapy. Methods: Ninety patients with advanced gastric cancer who had undergone radical surgery and received 5-FU-based adjuvant chemotherapy were included in this study. All patients underwent a 44-months minimum follow-up time. Lymphocyte genomic DNA was extracted from peripheral blood samples of the patients. Genotypes of variable number of tandem repeat (VNTR) and G/C single nucleotide polymorphism (SNP) in the TS 5’-UTR and 6bp deletion polymorphism in the 3’-UTR were determined by PCR and PCR-RFLP. According to previous studies the VNTR and the SNP were combined and the genotypes were grouped as follows; 5’-high (3G/3G, 3G/3C, 2R/3G) and 5’-low (2R/2R, 2R/3C, 3C/3C). Genotypes in 3’-UTR were also classified as follows; 3’-high (ins6/ins6) and 3’-low (del6/ins6, del6/del6). Results: There were no significant relationships between clinico-pathologic features and each TS polymorphism. Ten patients were 5’-high/3’-high (100% relapse/death), 36 patients were 5’-high/3’-low (67% relapse/death, 33% disease-free), 19 patients were 5’-low/3’-high (58% relapse/death, 42% disease-free), 25 patients were 5’-low/3’-low (36% relapse/death, 64% disease-free). Patients with 5’-low/3’-low genotypes showed significantly better outcome than those with 5’-high/3’-low and 5’-high/3’-high genotypes in regard to both 3-year disease-free and overall survival rates. The presence of at least one high TS expression genotype showed independent adverse prognostic role in multivariate analysis. Conclusions: TS polymorphisms showed prognostic influence in the studied population of gastric cancer patients. Analysis of combined TS5’- and TS3’-UTR genotypes may be useful for improving adjuvant treatment strategies with tailored chemotherapy. No significant financial relationships to disclose.