Abstract
BackgroundThe underlying biological mechanisms through which epidemiologically defined breast cancer risk factors contribute to disease risk remain poorly understood. Identification of the molecular changes associated with cancer risk factors in normal tissues may aid in determining the earliest events of carcinogenesis and informing cancer prevention strategies.MethodsHere we investigated the impact cancer risk factors have on the normal breast epigenome by analyzing DNA methylation genome-wide (Infinium 450 K array) in cancer-free women from the Susan G. Komen Tissue Bank (n = 100). We tested the relation of established breast cancer risk factors, age, body mass index, parity, and family history of disease, with DNA methylation adjusting for potential variation in cell-type proportions.ResultsWe identified 787 cytosine-guanine dinucleotide (CpG) sites that demonstrated significant associations (Q value <0.01) with subject age. Notably, DNA methylation was not strongly associated with the other evaluated breast cancer risk factors. Age-related DNA methylation changes are primarily increases in methylation enriched at breast epithelial cell enhancer regions (P = 7.1E-20), and binding sites of chromatin remodelers (MYC and CTCF). We validated the age-related associations in two independent populations, using normal breast tissue samples (n = 18) and samples of normal tissue adjacent to tumor tissue (n = 97). The genomic regions classified as age-related were more likely to be regions altered in both pre-invasive (n = 40, P = 3.0E-03) and invasive breast tumors (n = 731, P = 1.1E-13).ConclusionsDNA methylation changes with age occur at regulatory regions, and are further exacerbated in cancer, suggesting that age influences breast cancer risk in part through its contribution to epigenetic dysregulation in normal breast tissue.
Highlights
The underlying biological mechanisms through which epidemiologically defined breast cancer risk factors contribute to disease risk remain poorly understood
In another candidate gene study of normal breast tissue, the same group observed that RASSF1 methylation is associated with breast cancer risk level, and that increasing parity is associated with decreased APC methylation [10]
Our analysis revealed that further DNA methylation alterations to these genomic regions in preinvasive and invasive disease may contribute to the restriction of cellular differentiation and disruption of transcriptional control observed in cancerous lesions
Summary
The underlying biological mechanisms through which epidemiologically defined breast cancer risk factors contribute to disease risk remain poorly understood. Candidate gene studies in normal breast tissues indicate that DNA methylation changes are related to age and to other known breast cancer risk factors. Women without breast cancer, but at high risk (Gail model score) are more likely to have aberrant methylation of the tumor suppressor genes APC and RASSF1 compared with women at low risk [9] In another candidate gene study of normal breast tissue, the same group observed that RASSF1 methylation is associated with breast cancer risk level, and that increasing parity is associated with decreased APC methylation [10]. Preliminary results from another study provide evidence that genome-wide age-related DNA methylation changes in tumor-adjacent normal breast tissues are more likely to be altered in breast tumors than in randomly selected regions [12]. The relationship between breast cancer risk factors and DNA methylation changes in normal breast tissue from disease-free subjects remains unclear
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