Abstract 891: The association of single nucleotide polymorphisms in folate metabolism genes with hypermethylation patterns in smokers at high risk for lung cancer

Abstract

Hypermethylation of promoter regions serve as potential biomarkers for the early detection of lung cancer. Because folate metabolism is necessary for nucleotide synthesis and DNA methylation reactions, that when perturbed, may both contribute to the development of cancer, hypermethylation of promoter regions in folate metabolism genes may be particularly important to explore. Dietary folate was recently found to protect against gene promoter hypermethylation patterns. This study investigated the association of functional and haplotype tagging single nucleotide polymorphisms (SNPs) in folate metabolism genes with promoter hypermethylation in sputum cell DNA from a cohort of current and former smokers (n=937). This cohort was a subset of the Lovelace Smokers’ Cohort of approximately 2000 high risk current and former smokers who were non-Hispanic white and for whom a complete methylation panel was obtained. Methylation panel status from a 12 gene panel was dichotomized into high and low methylation based on a cutoff of the number of genes methylated (> = 3 genes for women and > = 4 genes for men were categorized as high). Lymphocyte DNA was interrogated on a 96 SNP Illumina Goldengate platform. A SNP in the cystathionine-beta synthase gene (CBS), that converts homocysteine to cystathionine, was found to be significantly associated with gene promoter hypermethylation. Analyses used logistic regression and adjusted for multiple comparisons. There was an interaction between gender and CBS (p<0.0001), so we conducted a stratified analysis by gender. Males with the variant allele had an increased risk of methylation (OR = 3.61; 95% CI: 1.71, 7.64); p<0.001) and females with the variant allele had a decreased risk for methylation (OR = 0.64; 95% CI: 0.40, 1.00; p=0.05). A 20% reduction in CBS gene transcription was seen in bronchial epithelial cells heterozygous for the CBS variant allele compared to cells without the variant allele but was not statistically significant. Epidemiological studies have shown that men have higher levels of homocysteine compared to women but the mechanisms regulating this difference are not known. This study shows that a SNP in the CBS gene is associated with methylation patterns in smokers at high risk to develop lung cancer and differs by gender. This work may further help to elucidate the differences in lung cancer risk by gender. Grant Support: This work is supported by K01CA128823 NCI and R01CA097356 NCI Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 891. doi:10.1158/1538-7445.AM2011-891