Abstract 2633: Single nucleotide polymorphisms in one carbon metabolism genes are associated with methylation patterns and plasma metabolites in high risk smokers based on gender

Abstract

Abstract Lung cancer is the leading cause of cancer related deaths and most lung cancers are detected at a late stage. Gene promoter hypermethylation is now regarded as a promising biomarker to identify early risk and progression of lung cancer. The one carbon metabolism pathway is postulated to affect DNA methylation because it is necessary for the generation of S-adenosyl methionine or (SAM), the methyl donor for cellular DNA methylation reactions, through complex interactions with metabolites including folate, homocysteine, and methionine. This study investigated the association of single nucleotide polymorphisms (SNPs) in one carbon metabolism related genes with DNA promoter hypermethylation in sputum cell DNA from current and former smokers in the Lovelace Smokers Cohort (n=907). The association of SNPs with methylation was analyzed by logistic regression using gender specific high and low methylation cutoffs from a 12 gene methylation panel as the outcome. SNPs in the cystathionine beta-synthase (CBS) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) genes were found to be statistically associated with methylation in a gender specific fashion (CBS SNP, OR=4.9; CI: 1.98, 12.2, p=.0006 in males) and (MTRR SNP, OR= 0.57, CI: 0.42, 0.77, p=0.0003 in females). Plasma homocysteine levels and the ratio of homocysteine to cystathionine increased in male samples with heterozygous or homozygous minor alleles of the CBS SNP compared to male samples with homozygous common alleles (n=86). This study suggests that SNPs in the CBS and MTRR genes are associated with methylation patterns in smokers by gender. The CBS SNP may be important in regulating plasma homocysteine and cystathionine levels that could theoretically mediate the aberrant DNA methylation in smokers at high risk to develop lung cancer. Grant Support: This work is supported by K01CA128823 NCI (Flores) and R01CA097356 NCI (Belinsky). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2633. doi:1538-7445.AM2012-2633