Research Article: Reproductive characteristics modify the association between global DNA methylation and breast cancer risk in a population-based sample of women

Date Published: February 14, 2019

Publisher: Public Library of Science

Author(s): Lindsay J. Collin, Lauren E. McCullough, Kathleen Conway, Alexandra J. White, Xinran Xu, Yoon Hee Cho, Sumitra Shantakumar, Susan L. Teitelbaum, Alfred I. Neugut, Regina M. Santella, Jia Chen, Marilie D. Gammon, Aamir Ahmad.


DNA methylation has been implicated in breast cancer aetiology, but little is known about whether reproductive history and DNA methylation interact to influence carcinogenesis. This study examined modification of the association between global DNA methylation and breast cancer risk by reproductive characteristics. A population-based case-control study assessed reproductive history in an interviewer-administered questionnaire. Global DNA methylation was measured from white blood cell DNA using luminometric methylation assay (LUMA) and pyrosequencing assay (long interspersed elements-1 (LINE-1). We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among 1 070 breast cancer cases and 1 110 population-based controls. Effect modification was assessed on additive and multiplicative scales. LUMA methylation was associated with elevated breast cancer risk across all strata (comparing the highest to the lowest quartile), but estimates were higher among women with age at menarche ≤12 years (OR = 2.87, 95%CI = 1.96–4.21) compared to >12 years (OR = 1.66, 95%CI = 1.20–2.29). We observed a 2-fold increase in the LUMA methylation-breast cancer association among women with age at first birth >23 years (OR = 2.62, 95%CI = 1.90–3.62) versus ≤23 years (OR = 1.32, 95% CI = 0.84–2.05). No modification was evident for parity or lactation. Age at menarche and age at first birth may be modifiers of the association between global DNA methylation and breast cancer risk.

Partial Text

Breast cancer remains the most commonly diagnosed invasive cancer among women in the United States [1]. Breast carcinogenesis is a multi-stage process involving both genetic and epigenetic changes [2], the latter defined as changes in gene expression, independent of modifications to the gene sequence [3]. Epigenetic aberrations have been implicated in breast carcinogenesis [4–6] and, unlike genetic alterations, these modifications may be altered across the lifespan by both exogenous and endogenous factors [7]. One commonly studied epigenetic modification is DNA methylation, characterized as the addition of a methyl group (-CH3) to the 5-carbon position of cytosine CpG dinucleotides [8]. DNA methylation is a regulatory mechanism for gene expression and may influence cancer development through activation or silencing of genes involved in tumorigenesis [8]. In addition to gene-specific DNA methylation, global DNA hypomethylation in regions that are normally methylated (i.e., tandem repeats or transposable elements) can lead to genomic instability and oncogene expression in breast tissue [8]. We previously reported that breast cancer risk was increased among women in the highest level of luminometric methylation assay (LUMA), but no association was observed when we considered long interspersed elements-1 (LINE-1) methylation in white blood cell (WBC) DNA [9].

Existing resources from the population-based case-control Long Island Breast Cancer Study Project (LIBCSP) were used to conduct our ancillary study. Details of participant recruitment, study design, and cohort characteristics have been described elsewhere [18]. All participating institutions obtained Institutional Review Board approval.

Among control women, we observed no associations between any reproductive characteristic and LUMA or LINE-1 methylation levels. Observed estimates were at or near the null, with all confidence intervals including the null (S1 Table).

In this population-based case-control study, we found that the association between global methylation, measured by LUMA in peripheral blood DNA, and breast cancer risk may depend on select reproductive characteristics, namely age at menarche and age at first birth (but not parity or lactation). Specifically, among women with age at menarche ≤12 years, there was nearly a 200% increase in breast cancer risk in association with high LUMA methylation levels; in contrast, the LUMA methylation-breast cancer association was only modestly increased by 66% among women with age at menarche >12 years (multiplicative interaction p = 0.05). Similarly, among women with a first birth >23 years, the association between high LUMA methylation levels and breast cancer risk was increased by greater than 150%; whereas among women with a first birth ≤23 years, the LUMA methylation-breast cancer association was increased by only 32% (multiplicative interaction p value = 0.02) No modification of the LINE-1 methylation-breast cancer association was observed by any of the four reproductive characteristics considered.

Using resources from a large population-based case-control study, we observed that high methylation levels, assessed using the LUMA platform, were differentially associated with breast cancer risk among women with an earlier age at menarche and a later age at first birth. This study provides etiologic insight into how age-related reproductive factors may influence breast cancer risk through its interaction with the DNA methylome. Our findings may also help in the identification of an early biomarker among women who are at an increased risk of breast cancer based on their reproductive history.




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