Document Type

Article

Publication Date

7-10-2017

Publication Title

Breast cancer research : BCR

Keywords

JGM, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Biopsy, Breast Neoplasms, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Genomics, Humans, Mammary Glands, Human, Middle Aged, Neoplasm Invasiveness, Regulatory Sequences, Nucleic Acid, Reproducibility of Results, Risk Factors, Young Adult

JAX Source

Breast Cancer Res . 2017 Jul 10;19(1):81.

Volume

19

Issue

1

First Page

81

Last Page

81

ISSN

1465-542X

PMID

28693600

DOI

10.1186/s13058-017-0873-y

Grant

The research reported in this publication was supported by the Center for Molecular Epidemiology COBRE program with grant funds from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health under award number P20 GM104416 (PI: Margaret R. Karagas). This work was supported by the National Institutes of Health grant numbers R01DE022772 to BCC and R01MH094609 to EAH.

Abstract

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.

Comments

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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