ABSTRACT

Background: Altered DNA methylation may be an intermediate phenotype between breast cancer risk factors and disease. Mammographic density is a strong risk factor for breast cancer. However, no studies to date have identified an epigenetic signature of mammographic density. We performed an epigenome-wide association study of mammographic density.

Methods: White blood cell DNA methylation was measured for 385 postmenopausal women using the Illumina Infinium MethylationEPIC BeadChip array. Differential methylation was assessed using genome-wide, probe-level, and regional analyses. We implemented a resampling-based approach to improve the stability of our findings.

Results: On average, women with elevated mammographic density exhibited DNA hypermethylation within CpG islands and gene promoters compared to women with lower mammographic density. We identified 250 CpG sites for which DNA methylation was significantly associated with mammographic density. The top sites were located within genes associated with cancer, including HDLBP, TGFB2, CCT4, and PAX8, and were more likely to be located in regulatory regions of the genome. We also identified differential DNA methylation in 37 regions, including within the promoters of PAX8 and PF4, a gene involved in the regulation of angiogenesis. Overall, our results paint a picture of epigenetic dysregulation associated with mammographic density.

Conclusion: Mammographic density is associated with differential DNA methylation throughout the genome, including within genes associated with cancer. Our results suggest the potential involvement of several genes in the biological mechanisms behind differences in breast density between women. Further studies are warranted to explore these potential mechanisms and potential links to breast cancer risk.

摘要

背景：改变的 DNA 甲基化可能是乳腺癌风险因素和疾病之间的中间表型。乳腺钼靶密度是乳腺癌的一个重要危险因素。然而，迄今为止，还没有研究确定乳房 X 线密度的表观遗传特征。我们对乳房 X 线密度进行了表观基因组范围的关联研究。

方法：使用 Illumina Infinium MethylationEPIC BeadChip 阵列测量 385 名绝经后妇女的白细胞 DNA 甲基化。使用全基因组、探针水平和区域分析评估差异甲基化。我们实施了一种基于重采样的方法来提高我们研究结果的稳定性。

结果：平均而言，与乳腺钼靶密度较低的女性相比，乳腺钼靶密度升高的女性在 CpG 岛和基因启动子内表现出 DNA 高甲基化。我们确定了 250 个 CpG 位点，其 DNA 甲基化与乳腺 X 线密度显着相关。顶部位点位于与癌症相关的基因中，包括HDLBP、TGFB2、CCT4和PAX8，并且更有可能位于基因组的调控区域。我们还鉴定了 37 个区域的差异 DNA 甲基化，包括PAX8和PF4的启动子，这是一种参与调节血管生成的基因。总体而言，我们的结果描绘了与乳房 X 线密度相关的表观遗传失调的图景。

结论：乳房X线照片密度与整个基因组的差异DNA甲基化相关，包括与癌症相关的基因内。我们的研究结果表明，女性乳房密度差异背后的生物学机制可能涉及多个基因。需要进一步的研究来探索这些潜在的机制和与乳腺癌风险的潜在联系。