Polymorphism in Thymidylate Synthase Gene Predicts Survival and Toxicity in North Indian Lung Cancer Patients Undergoing Platinum-Based Doublet Chemotherapy.

Abstract

With an estimated 1.8 million deaths, lung cancer is one of the widely reported malignancies, with substantial morbidity and mortality rates. Thymidylate synthase (TS) is an important drug target for platinum-based doublet chemotherapy as it is the only de novo source of thymidylate production in the cell. TS polymorphisms in the 5'UTR of Thymidylate synthase enhancer region (TSER) 2R/3R and 3'- UTR 1494del6 are investigated in this study. A total of 700 lung cancer patients with platinum-based doublet chemotherapy were recruited in this study. TSER (2R/3R) and TS 1494del6 polymorphisms in North Indian lung cancer patients were examined, and statistical analysis was performed. According to our findings, patients with the wild genotype (2R/2R) for the TSER polymorphism had a longer median survival time as compared to patients harboring the mutant type genotype (3R/3R) [MST=9.77 vs. 7.57 months; p=0.04]. On the contrary, patients with the mutant 14946del6 polymorphism (-6/-6) had a longer survival time than patients with the wild-type genotype (+6/+6) [MST=7.23 vs. 9 months]. Further, our findings elucidated that the patients with heterozygous genotype (2R3R) for TSER polymorphism had a 2.30-fold increased risk of developing leukopenia (AOR=2.30, 95% CI=0.96-5.52; p=0.05). A substantial risk of 5.14-fold constipation was found in heterozygous genotype (2R3R) when intermediate grade 2 toxicity was compared with low toxicity (grade 1) (p=0.007).An increased risk of nausea/vomiting was observed in patients with mutant genotype (-6/-6bp) for 1494 ins/del6 polymorphism compared to patients with wild-type genotype (+6/+6bp) (AOR= 2.77; 95%CI=1.10-6.96, p=0.03). According to our findings, TSER and the 1494del6 polymorphism may operate as a prognostic marker in lung cancer patients receiving platinum-based chemotherapy. Furthermore, TS polymorphisms may influence the onset of platinum-related toxicity, such as hematological and gastrointestinal toxicity. These findings might facilitate therapeutic decisions for individualized therapy in lung cancer patients.