Abstract
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.
Highlights
Breast cancer remains the most commonly diagnosed invasive cancer among women in the United States [1]
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]
We observed no associations between any reproductive characteristic and LUMA or LINE-1 methylation levels
Summary
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 [4,5,6] 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]. 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]
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