Abstract 3640: Age-related DNA methylation in normal breast tissues.

Abstract

Abstract Age-related DNA methylation in normal breast tissues It is well established that age is a key risk factor for breast cancer, with increasing incidence associated with older age. Epigenetic mechanisms, such as DNA methylation alterations, may contribute to age-related increases in breast cancer risk. Altered patterns of DNA methylation can modify the regulation of gene expression or expression potential, and DNA methylation alterations are frequently observed in the early stages of breast tumorigenesis. However, genome-wide interindividual variation in normal breast DNA methylation has not been well characterized for its relation with age and other key breast cancer risk factors. To investigate the relationship between age and DNA methylation in normal breast tissues, we first performed a meta-analysis using two independent data sets GSE32393 (n=23) and GSE31979 (n=15), from the Gene Expression Omnibus (GEO) database. For each of the considered datasets, genome-wide DNA methylation was assessed using the Illumina Infinium HumanMethylation27 Beadchip, which profiles the methylation status of ∼27,000 CpG loci, associated with >14,000 genes. Associations between DNA methylation and age were examined by fitting a series of linear regression models to arcsine square root transformed average beta values for all CpG loci in both data sets. Between these data sets, 204 CpG loci were significantly and consistently associated (P < 0.05) with subject age. Relative to the distribution of CpG loci on the array, we observed a significant enrichment of age-related DNA methylation patterns at CpG loci residing in CpG islands (P = 8.7e-6). Further, compared to non-island CpGs, loci in CpG islands were significantly more likely to exhibit increased age-related methylation (P = 0.008). To validate observed age-related DNA methylation, we performed bisulfite pyrosequencing of selected CpGs in an independent set of normal breast tissues (n=20) obtained through the National Disease Research Interchange. Our findings demonstrate consistent age-related methylation changes in normal breast tissue that may represent early events contributing to breast carcinogenesis and additional investigation for enrichment of local sequence and bioinformatic features near CpGs with age-related methylation is ongoing. This work contributes to the understanding of epigenetic mechanisms by which age serves as a major risk factor in the development of breast cancer. Citation Format: Kevin C. Johnson, Amanda K. Jensen, Megan A. Murphy, Devin C. Koestler, Brock C. Christensen. Age-related DNA methylation in normal breast tissues. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3640. doi:10.1158/1538-7445.AM2013-3640