Abstract
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.
Highlights
Breast cancer is a heterogeneous disease, comprised of different clinical subtypes linked to disparate prognosis
These CpG dinucleotides (CpGs) were mapped to 1,292 miRNA genes, which correspond to 2,035 unique mature miRNAs based in the latest release of miRBase version 22
As no known studies have examined genome-wide DNA methylation patterns of miRNA encoding genes in breast tumors from African ancestry (AA) populations, and there is a clear pattern of estrogen receptor negative (ER-)subtype differences (Fig 1), in the current study, we focused on analyses to identify differentially methylated loci (DML: |delta β| 0.10; false discovery rate (FDR)
Summary
Breast cancer is a heterogeneous disease, comprised of different clinical subtypes linked to disparate prognosis. Specific methylation patterns have been associated with high tumor grade and ER negativity of breast cancer [4, 7,8,9]. In our own studies and others, analyses restricted to CpG dinucleotides (CpGs) within and nearby PCGs, show differences in DNA methylation patterns in tumors by ER status and between AA and EA women [10,11,12,13]. These results suggest that aggressive breast cancer subtypes may be related to altered gene methylation, and that methylation patterns may differ by ancestry
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