Environmental Exposure and DNA Damage

National Institute Of Environmental Health Sciences

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Abstract

The biological mechanisms driving associations between alcohol consumption and chronic diseases may include epigenetic modification of DNA methylation. We explored the hypothesis that alcohol consumption is associated with methylation in an epigenome-wide association study of blood and normal breast tissue DNA. Infinium HumanMethylation450 BeadChip array data on blood DNA methylation was examined in a discovery set of 2,878 white Non-Hispanic women from the Sister Study who provided detailed questionnaire information on lifetime alcohol use. Robust linear regression modeling was used to identify significant associations (at False Discovery Rate q <0.05) between the number of alcoholic drinks per week and DNA methylation at 5,458 CpG sites. Associations were replicated (p<0.05) for 677 CpGs in an independent set of 187 Sister Study blood DNA samples, and for 628 CpGs in an independent set of 171 normal breast DNA samples. In total 1,207 CpGs were replicated in either blood or normal breast with 98 CpGs replicated in both tissues. In addition, we found that high alcohol consumption was associated with a significant decrease in global methylation as measured by the average of CpGs on the entire array. Peripheral blood DNA methylation may be associated with breast cancer, but studies of candidate genes, global, and genome-wide DNA methylation have been inconsistent. We performed a large epigenome-wide study using prospectively collected samples from the Sister Study, including 1,552 cases and a random sample of the 1224 women from the cohort. We identified 9,601 CpG markers associated with invasive breast cancer at false discovery rate q < 0.01 and replicated 2,095 of these in an independent dataset,; 144 of these replicated the CpGs were significant at strict Bonferroni threshold (10-7) in our study. . Most of the top differentially methylated CpGs (dmCpGs) showed lower methylation in invasive cases and inversely correlated with time-to-diagnosis. Women who developed ductal carcinoma in situ had profiles in between invasive cases and non-cases. Based on ENCODE annotation, dmCpGs with lower methylation in cases occur at non-island sites enriched for the H3K36me3 histone mark, whereas sites with higher methylation in cases occur at CpG islands enriched for H3K4me3. Pathway analysis shows enrichment of breast cancer-related gene pathways, and dmCpGs are overrepresented in known breast cancer susceptibility genes.