Abstract 288: DNA methylation patterns in peripheral blood and the relationship with cancer susceptibility loci at chromosome 8q24

Abstract

Abstract Chromosome 8q24 has emerged as an important region for genetic susceptibility to several cancers, but little is known about the contribution of DNA methylation in this region. To explore the extent of variation in DNA methylation at 8q24 in peripheral blood and its relationship with genetic variation in the region, we conducted a cross-sectional study using blood samples from 80 non-Hispanic Caucasian males in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Specifically, we aimed to evaluate between-individual variation in DNA methylation levels at specific CpG sites at 8q24 and to investigate the underlying genetic structure in the region by examining correlations for DNA methylation levels with each other and with the established cancer susceptibility SNPs at 8q24. We quantified DNA methylation levels at 145 CpG sites nearby cancer susceptibility single nucleotide polymorphisms (SNPs) at 8q24 or the MYC oncogene using pyrosequencing of bisulfite-treated DNA, which is considered a highly sensitive method to detect differences in DNA methylation levels between individuals. We calculated pairwise Spearman correlations (rho), adjusting for multiple testing using the False Discovery Rate (FDR) method. We identified a large number of CpG sites that were reproducible and demonstrated moderate to high between-individual variation in our study population. Among these CpG sites, some sites within or nearby MYC and POU5F1B were strongly correlated with one another (highest rho=0.74), suggesting a coordination of DNA methylation levels in gene regions. Moreover, we observed strong correlations between several CpG sites and some of the known cancer susceptibility SNPs at 8q24. Some of the correlations remained statistically significant after adjustment for multiple comparisons, including a CpG site and an established prostate cancer SNP in the long non-coding RNA PRNCR1 (Chr8:128167809 and rs1456315, rho=0.52; p-value=1.4x10-6; FDR-adjusted p-value=0.002) and a CpG site (Chr8:128498051) in POU5F1B and the known prostate/colorectal cancer SNP rs6983267 (rho=0.46; p-value=2.0x10-5; FDR-adjusted p-value=0.01). This is the first study to report associations between DNA methylation levels at 8q24 in peripheral blood and 8q24 cancer susceptibility SNPs, suggesting that DNA methylation at this important susceptibility locus may contribute to risk. Additional studies are needed to clarify the relationship between genetic and epigenetic variation at 8q24 and cancer risk. Citation Format: Kathryn Hughes Barry, Lee Moore, Joshua Sampson, Liying Yan, Ann Meyer, Charles C. Chung, Meredith Yeager, Laufey Amundadottir, Sonja I. Berndt. DNA methylation patterns in peripheral blood and the relationship with cancer susceptibility loci at chromosome 8q24. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 288. doi:10.1158/1538-7445.AM2014-288