Title : Polymorphism in Thymidylate Synthase gene predicts survival and toxicity in North Indian lung cancer patients undergoing platinum-based doublet chemotherapy
Abstract:
Lung cancer is one of the most widely reported tumors having high morbidity and mortality rates with an estimated 1.8 million fatalities. Thymidylate synthase (TS) is an important target for chemotherapy treatments and platinum-based therapies since it is the cell's only de novo source of thymidylate production. TS polymorphisms in the TS enhancer region (TSER) 2R/3R and TS 1494del6 in the 5' and 3’-untranslated regions (UTRs) are investigated in this study. A total of 700 lung cancer patients with platinum-based chemotherapy were recruited in the study. Polymorphisms of TSER (2R/3R) and TS 1494del6 in North Indian lung cancer patients were assessed and statistical analysis were carried out. Our data observed that patients with wild genotype (2R/2R) for TSER polymorphism showed higher trend of median survival time compared to patients bearing the mutant type genotype (3R/3R) [MST=9.77 vs. 7.57 months; p=0.04]. Patients with mutant genotype (-6/-6) for 14946del6 polymorphism showed higher survival time compared to patients bearing the wild type genotype (+6/+6) [MST=7.23 vs. 9 months]. Further, we observed 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) when compared to the subjects with wild type genotype (2R2R). 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). Our data suggest that TSER and 1494del6 polymorphism act as a predictive marker in lung cancer patients treated with platinum chemotherapy. Also, TS polymorphisms might impact the development of platinum-related toxicities such hematological and gastrointestinal toxicity. These findings might facilitate therapeutic decisions for individualized therapy in lung cancer patient.
