Thymidylate synthase polymorphisms and its mRNA expression levels as independent chemo-predictive markers in esophageal adenocarcinoma patients receiving 5-fluorouracil chemotherapy

Abstract

4063 Background: Thymidylate synthase (TS) has either a two or three 28bp tandemly repeated sequence in the 5’ untranslated (UTR) region. The triple repeat allele (3R) is classified into 2 subgroups (3RG, 3RC) according to a G/C polymorphism in the 3R sequences. Another polymorphism is a 6bp deletion in the 3’-UTR region. The genotype with either 3RG allele or 6bp insertion allele has been reported to be associated with high TS expression and chemoresistance to 5-FU. Methods: 83 patients with esophageal adenocarcinoma were assessed. Thirty-four had received 5-FU containing chemotherapy (16 adjuvant therapy, 12 upon recurrence, 3 both adjuvant and recurrence, 3 neoadjuvant) and 49 were treated with surgery alone. Surgically resected tumor tissues were analyzed for TS genotype and TS mRNA expression using a quantitative real-time RT-PCR method after microdissection. Results: No survival difference was seen between the patients with 3RG allele (3RG group) and non-3RG group among surgery-alone patients. However, among patients with a history of 5-FU-based chemotherapy, the non-3RG group showed significantly better overall survival compared to the 3RG group (p = 0.02). Moreover, whereas chemotherapy produced a significant increase in survival for the non-3RG group patients, those in the 3RG group obtained no survival benefit from chemotherapy. Patients with low TS mRNA levels had significantly better survival than the patients with high TS mRNA levels (p = 0.03) among chemotherapy-treated patients, despite the fact that there was no difference of median TS mRNA levels between 3RG and non-3RG group. Those who had both the non-3RG genotype and low TS mRNA levels obtained a significantly better survival benefit from chemotherapy than others (p = 0.02). The 3’-UTR polymorphism did not appeared to be associated with overall survival. Conclusions: The status of the TS 5’-UTR polymorphism and TS mRNA expression are independent predictive markers for survival benefit from 5-FU-based therapy in patients with esophageal adenocarcinoma. [Table: see text]