title: DNA methylation levels at chromosome 8q24 in peripheral blood are associated with 8q24 cancer susceptibility loci.
abstract: Chromosome 8q24 has emerged as an important region for genetic susceptibility to various cancers, but little is known about the contribution of DNA methylation at 8q24. To evaluate variability in DNA methylation levels at 8q24 and the relationship with cancer susceptibility single nucleotide polymorphisms (SNPs) in this region, we quantified DNA methylation levels in peripheral blood at 145 CpG sites nearby 8q24 cancer susceptibility SNPs or MYC using pyrosequencing among 80 Caucasian men in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. For the 60 CpG sites meeting quality control, which also demonstrated temporal stability over a 5-year period, we calculated pairwise Spearman correlations for DNA methylation levels at each CpG site with 42 8q24 cancer susceptibility SNPs. To account for multiple testing, we adjusted P values into q values reflecting the false discovery rate (FDR). In contrast to the MYC CpG sites, most sites nearby the SNPs demonstrated good reproducibility, high methylation levels, and moderate-high between-individual variation. We observed 10 statistically significant (FDR < 0.05) CpG site-SNP correlations. These included correlations between an intergenic CpG site at Chr8:128393157 and the prostate cancer SNP rs16902094 (ρ = -0.54; P = 9.7 × 10(-7); q = 0.002), a PRNCR1 CpG site at Chr8:128167809 and the prostate cancer SNP rs1456315 (ρ = 0.52; P = 1.4 × 10(-6); q = 0.002), and two POU5F1B CpG sites and several prostate/colorectal cancer SNPs (for Chr8:128498051 and rs6983267, ρ = 0.46; P = 2.0 × 10(-5); q = 0.01). This is the first report of correlations between blood DNA methylation levels and cancer susceptibility SNPs at 8q24, suggesting that DNA methylation at this important susceptibility locus may contribute to cancer risk.
authors.affiliation: Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland. barrykh@mail.nih.gov.
authors.forename: Kathryn Hughes
authors.initials: KH
authors.lastname: Barry
authors.affiliation: Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
authors.affiliation: Biostatistics Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Joshua
authors.initials: J
authors.lastname: Sampson
authors.affiliation: EpigenDx, Inc., Hopkinton, Massachusetts.
authors.forename: Liying
authors.initials: L
authors.lastname: Yan
authors.affiliation: EpigenDx, Inc., Hopkinton, Massachusetts.
authors.forename: Ann
authors.initials: A
authors.lastname: Meyer
authors.affiliation: Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Oler
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chung
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Laufey
authors.initials: L
authors.lastname: Amundadottir
authors.affiliation: Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
mesh_terms: D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics*; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
chemical_list: D004273:DNA, Neoplasm