Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States of America.
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States of America.
PLoS One. 2021 Mar 30;16(3):e0249229. doi: 10.1371/journal.pone.0249229. eCollection 2021.
Aggressive high-grade, estrogen receptor negative (ER-) breast cancer is more common among American women of African ancestry (AA) than those of European ancestry (EA). Epigenetic mechanisms, particularly DNA methylation and altered microRNA (miRNA) expression, may contribute to racial differences in breast cancer. However, few studies have specifically characterized genome-wide DNA methylation-based modifications at the miRNA level in relation to ER+ and ER- subtype, and their functional role in the regulation of miRNA expression, especially among high risk AA women. In this study, we evaluated DNA methylation patterns of miRNA encoding genes and their effect on expression in breast tumors from both AA and EA women. The genome-wide methylation screen identified a total of 7,191 unique CpGs mapped to 1,292 miRNA genes, corresponding to 2,035 unique mature miRNAs. We identified differentially methylated loci (DMLs: (|delta β|)>0.10, FDR<0.05) between ER- and ER+ tumor subtypes, including 290 DMLs shared in both races, 317 and 136 were specific to AA and EA women, respectively. Integrated analysis identified certain DMLs whose methylation levels were significantly correlated with the expression of relevant miRNAs, such as multiple CpGs within miR-190b and miR-135b highly negatively correlated with their expression. These results were then validated in the TCGA dataset. Target prediction and pathway analysis showed that these DNA methylation-dysregulated miRNAs are involved in multiple cancer-related pathways, including cell cycle G1-S growth factor regulation, cytoskeleton remodeling, angiogenesis, EMT, and ESR1-mediated signaling pathways. In summary, our results suggest that DNA methylation changes within miRNA genes are associated with altered miRNA expression, which may contribute to the network of subtype- and race-related tumor biological differences in breast cancer. These findings support the involvement of epigenetic regulation of miRNA expression and provide insights into the relations of clinical-relevant miRNAs to their target genes, which may serve as potential preventative and therapeutic targets.
侵袭性高级别、雌激素受体阴性（ER-）乳腺癌在非洲裔美国女性（AA）中比欧洲裔美国女性（EA）更为常见。表观遗传机制，特别是 DNA 甲基化和 miRNA（miRNA）表达的改变，可能导致乳腺癌的种族差异。然而，很少有研究专门描述与 ER+和 ER-亚型相关的 miRNA 水平的全基因组 DNA 甲基化修饰，以及它们在 miRNA 表达调控中的功能作用，尤其是在高危 AA 女性中。在这项研究中，我们评估了来自 AA 和 EA 女性乳腺癌肿瘤中 miRNA 编码基因的 DNA 甲基化模式及其对 miRNA 表达的影响。全基因组甲基化筛选共鉴定了 7191 个独特的 CpG 映射到 1292 个 miRNA 基因，对应于 2035 个独特的成熟 miRNA。我们鉴定了 ER-和 ER+肿瘤亚型之间的差异甲基化位点（DML：(|delta β|)>0.10，FDR<0.05），包括在两个种族中共享的 290 个 DML、分别特属于 AA 和 EA 女性的 317 个和 136 个 DML。综合分析确定了某些 DML 的甲基化水平与相关 miRNA 的表达显著相关，例如 miR-190b 和 miR-135b 内的多个 CpG 与它们的表达呈高度负相关。这些结果随后在 TCGA 数据集得到验证。靶标预测和通路分析表明，这些 DNA 甲基化失调的 miRNA 参与多个癌症相关通路，包括细胞周期 G1-S 生长因子调控、细胞骨架重塑、血管生成、EMT 和 ESR1 介导的信号通路。总之，我们的研究结果表明，miRNA 基因内的 DNA 甲基化变化与 miRNA 表达的改变有关，这可能有助于乳腺癌中与亚型和种族相关的肿瘤生物学差异的网络。这些发现支持 miRNA 表达的表观遗传调控，并为临床相关 miRNA 与其靶基因的关系提供了新的见解，这可能成为潜在的预防和治疗靶点。
