Abstract 2759: Association between genetic variations in DNA damage response pathways and risk for gene methylation in sputum from smokers

Abstract

Abstract The detection of gene promoter hypermethylation in sputum containing exfoliated epithelial cells is a promising biomarker for detecting early incident lung cancer. Therefore, identifying factors that influence the propensity for this epigenetic process throughout the respiratory epithelium is a high priority. The genes and the pathways they modulate underlying the inter-individual susceptibility to DNA methylation remain largely elusive. Accumulating evidence from our group and others implicate DNA damage as an important step in the acquisition of de novo methylation. We hypothesized that genetic variations in genes (n=66) involved in carcinogen metabolism and DNA damage response, including DNA damage repair, cell cycle control, apoptosis, and methylation related pathways will be associated with gene methylation in sputum from lung-cancer free smokers. Three databases including HapMap Stage I database, University of Southern California DNA repair and Children Pulmonary Function Development Oligo Pool Assay (OPA) database, and NIBC dbSNPs database were used to select a comprehensive set of SNPs (OPA1, n=1536) to capture the major genetic variations in these genes. A pilot study for testing the association between these SNPs and risk for methylation was conducted in a subset of people (n=261) selected from Lovelace Smokers Cohort (LSR) based on their methylation index (8-gene panel). Two gene-based analyses were conducted to rank the genes and 683 tagging SNPs from the top 42 genes were selected based on the OPA1 and the HapMap Stage II databases and genotyped in all people (n=1177) with methylation data (12-gene panel) in baseline sputum samples in LSR. The effect of SNPs was tested under an additive inheritance model. A reproducible association was identified in SNPs from the TP53, GSTP1, LIG1, CASP8, BOK, and PMAIP1 genes between the pilot study and the entire study. Ongoing functional studies reveled an association between genotype and expression of LIG1 in bronchial epithelial cells from smokers. This study identified six genes involved in carcinogen detoxification and DNA damage response that were associated with risk for gene methylation in sputum from smokers. (Supported from National Cancer Institute R01 CA097356 and the State of New Mexico as a direct appropriation from the Tobacco Settlement Fund) 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 2759. doi:10.1158/1538-7445.AM2011-2759