Influence of Polymorphisms in MTHFR 677 C→T, TYMS 3R→2R and MTR 2756 A→G on NSCLC Risk and Response to Platinum-Based Chemotherapy in Advanced NSCLC

Abstract

Genetic factors may contribute to individual differences in cancer susceptibility, drug efficacy and toxicity. This study was designed to investigate the effects of the polymorphisms of methylenetetrahydrofolate reductase 677 C→T (MTHFR 677 C→T), thymidylate synthase (TYMS 3R→2R),and methionine synthase 2756 A→G (MTR 2756 A→G) on the risk of lung cancer and response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). We conducted a case-control study involving 438 NSCLC cases (including 101 follow-up cases) and 641 healthy controls in North China. Using a genetic model analysis, the polymorphism MTHFR 677 C→T showed a significantly increased risk for NSCLC in women but not in men, which was observed in the codominant model (CT vs CC adjusted odds ratio [OR] = 2.46; 95% confidence interval [CI]: 1.37-4.42; p = 0.003; TT vs CC adjusted OR: 2.04; 95% CI: 1.09-3.81; p = 0.03) and the dominant model (CT + TT vs CC adjusted OR: 2.30; 95% CI: 1.31-4.05; p = 0.004). In addition, we found that patients with the MTHFR 677 TT genotype showed a better response to platinum-based chemotherapy in the recessive model (TT vs CT + CC adjusted OR: 0.24; 95% CI: 0.09-0.68; p = 0.007), the generalized OR was 0.44 (0.22-0.88; p = 0.04). There were no significant associations of the polymorphisms of TYMS 3R→2R or MTR 2756 A→G with the risk of NSCLC or response to platinum-based chemotherapy in advanced NSCLC in any genetic model. Our results suggest that genetic polymorphisms of MTHFR 677 C→T may contribute to NSCLC development in Chinese women and could also influence treatment response for advanced NSCLC patients with platinum-based chemotherapy. Further studies with larger sample sizes are required to validate this association.