MTHFR Polymorphisms and Carcinogen DNA Damage in the Lung

Abstract

PP-30-157 Background/Aims: Methylenetetrahydrofolate reductase, MTHFR, is involved in the process of deoxyribonucleic acid (DNA) methylation and DNA synthesis, both implicated in carcinogenesis. Polymorphisms in MTHFR gene, C677T and A1298C, are associated with an elevated and/or decreased cancer risk, yet little is known about DNA damage in target lung tissue in human populations. Methods: DNA adducts in lung tissue and 5 polymorphic metabolic genotypes (GSTM1, GSTP1, GSTT1, NAT2, and MTHFR) were determined by using 32P-postlabeling assay and PCR techniques from 102 lung cancer patients undergoing resection for stage I-II lung cancer at Massachusetts General Hospital in Boston, MA. The independent effects of MTHFR polymorphisms on DNA lung adduct were assessed using multiple regression analysis, adjusting for covariates and other genotypes. Results: DNA lung adduct levels significantly increased by 64.4% (95% confidence interval [CI]: 3.0%–162.4%) for the 1298AC+CC genotype versus 1298AA and by 122.4% (95% CI: 1.7%–386.5%) for the combined heterozygous and homozygous variant genotypes versus 1298AA and 677CC, respectively. No association was seen with polymorphism of MTHFR C677T. After adjusting for potential confounders, as well as for other metabolic gene variants, the MTHFR 1298AC+CC had significantly enhanced levels of lung adducts by 109.9% (95% CI: 19.8%–267.8%). Conclusion: We found an association between increased DNA adduct levels with the MTHFR A1298C gene polymorphism, suggesting a potential effect of DNA methylation via MTHFR on DNA damage in the target lung tissue.