a Herbert Irving Comprehensive Cancer Center , Columbia University Medical Center , New York , NY.
b Department of Environmental Health Sciences , Mailman School of Public Health of Columbia University , New York , NY.
Epigenetics. 2018;13(3):240-250. doi: 10.1080/15592294.2018.1435243. Epub 2018 Apr 2.
Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6-13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Δ4.9%, P = 0.003) and SEC16B (Δ3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.
家族史是乳腺癌的一个已确立的风险因素，它既有遗传因素，也有环境因素的贡献。家庭中的共享环境以及表观遗传变化也可能受到遗传和环境的共同影响，这也可以解释癌症在家族中的聚集。表观遗传调控，如 DNA 甲基化，可以改变 DNA 片段的活性，而不改变其序列；在整个生命周期中经历的环境暴露可以诱导这种变化。然而，遗传-表观遗传相互作用，如甲基化数量性状基因座（mQTL；又名 meQTL）和单倍型依赖等位基因特异性甲基化（hap-ASM），也可以导致 DNA 甲基化模式的个体间差异。为了确定与乳腺癌易感性相关的差异甲基化区域（DMR），我们在来自 LEGACY 女孩研究的 426 名女孩（年龄 6-13 岁）的 29 个候选基因的白细胞 DNA 甲基化中检查了差异，其中 239 名有乳腺癌家族史（BCFH），187 名没有乳腺癌家族史。我们通过靶向大规模平行亚硫酸氢盐测序（bis-seq）测量了甲基化，并观察到两个基因中的 BCFH DMR：ESR1（Δ4.9%，P=0.003）和 SEC16B（Δ3.6%，P=0.026），这两个基因都与乳腺癌易感性和青春期发育有关。这些 DMR 显示出甲基化的个体间高度可变性，表明存在 mQTL/ hap-ASM。使用 bis-seq 扩增子中的单核苷酸多态性数据，我们在 SEC16B 中发现了强烈的 hap-ASM（等位基因特异性差异范围为 42%-74%）。这些发现表明，与乳腺癌易感性相关的基因中的差异甲基化可能在生命早期就存在，并且这些表观遗传差异的一些是由遗传因素引起的。
