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Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age.

ABSTRACT: The 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.Here 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.We 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).DNA 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.

SUBMITTER: Johnson KC

PROVIDER: S-EPMC5504720 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age.

Johnson Kevin C KC Houseman E Andres EA King Jessica E JE Christensen Brock C BC

Breast cancer research : BCR 20170710 1

<h4>Background</h4>The 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.<h4>Methods</h4>Here we investigated the impact cancer risk factors have on the normal breast epigenome by analyzing DNA methy ...[more]

PMID: 28693600

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Project description:BACKGROUND:DNA methylation (DNAm) age has been widely accepted as an epigenetic biomarker for biological aging. Emerging evidence suggests that DNAm age can be tissue-specific and female breast tissue ages faster than other parts of the body. The Horvath clock, which estimates DNAm age across multiple tissues, has been shown to be poorly calibrated in breast issue. We aim to develop a model to estimate breast tissue-specific DNAm age. METHODS:Genome-wide DNA methylation sequencing data were generated for 459 normal, 107 tumor, and 45 paired adjacent-normal breast tissue samples. We determined a novel set of 286 breast tissue-specific clock CpGs using penalized linear regression and developed a model to estimate breast tissue-specific DNAm age. The model was applied to estimate breast tissue-specific DNAm age in different breast tissue types and in tumors with distinct clinical characteristics to investigate cancer-related aging effects. RESULTS:Our estimated breast tissue-specific DNAm age was highly correlated with chronological age (r = 0.88; p = 2.9 × 10-31) in normal breast tissue. Breast tumor tissue samples exhibited a positive epigenetic age acceleration, where DNAm age was on average 7?years older than respective chronological age (p = 1.8 × 10-8). In age-matched analyses, tumor breast tissue appeared 12 and 13?years older in DNAm age than adjacent-normal and normal breast tissue (p = 4.0 × 10-6 and 1.0 × 10-6, respectively). Both HER2+ and hormone-receptor positive subtypes demonstrated significant acceleration in DNAm ages (p = 0.04 and 3.8 × 10-6, respectively), while no apparent DNAm age acceleration was observed for triple-negative breast tumors. We observed a non-linear pattern of epigenetic age acceleration with breast tumor grade. In addition, early-staged tumors showed a positive epigenetic age acceleration (p = 0.003) while late-staged tumors exhibited a non-significant negative epigenetic age acceleration (p = 0.10). CONCLUSIONS:The intended applications for this model are wide-spread and have been shown to provide biologically meaningful results for cancer-related aging effects in breast tumor tissue. Future studies are warranted to explore whether breast tissue-specific epigenetic age acceleration is predictive of breast cancer development, treatment response, and survival as well as the clinical utility of whether this model can be extended to blood samples.

Dataset Information

Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age.

Publications

Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age.

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