Abstract
BackgroundMicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women.MethodsUnder the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype.ResultsA novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26–1.65; p = 3.15 × 10−7; false discovery rate (FDR) = 0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR = 1.29, 95% CI = 1.16–1.44 (p = 4.18 × 10–6) and OR = 1.33, 95% CI = 1.17–1.51 (p = 1.6 × 10–5), respectively).ConclusionGermline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.
Highlights
MicroRNAs regulate gene expression and influence cancer
There are over 2500 identified human miRNAs [5] and each may bind to hundreds or even thousands of different target genes, coordinating expression of a large number of messenger RNA (mRNA); this makes them key players in gene regulatory networks [3]
All four single nucleotide polymorphisms (SNPs) reside in a genomic region that includes the first intron of the brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2), as well as the predicted primary transcript for MIR3065
Summary
MicroRNAs (miRNAs) regulate gene expression and influence cancer. Within the nucleus, a primary miRNA transcript (pri-miRNA)—usually several hundred nucleotides (nt) to greater than 1 megabase (Mb) in length—is cleaved to create a precursor miRNA (premiRNA) approximately 70 nt in length which folds to form a stem-loop intermediate. This intermediate is exported from the nucleus and further processed to a miRNA duplex, approximately 22 nt in length. Mature miRNAs bind to the 3’ untranslated region (UTR) of target genes to silence them by either translational repression or messenger RNA (mRNA) degradation [4]. There are over 2500 identified human miRNAs [5] and each may bind to hundreds or even thousands of different target genes, coordinating expression of a large number of mRNAs; this makes them key players in gene regulatory networks [3]
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