Bensen JT, et al. - Authors studied the germline miRNA variations related to breast cancer (BC) risk and tumor subtype among African-American (AA) women. Among AA women, an important role in BC development and heterogeneity could be played by MIR3065. The findings contributed to our knowledge of BC risk in AA women and how complicated evaluating variation in gene-dense regions of the human genome can be.

Methods

• In AA women, under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8,350 women, including 3,663 cases and 4,687 controls.
• Authors identified the primary miRNA sequence for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets.
• They conducted the association analysis using logistic regression for BC status overall and by tumor subtype.

Results

• As per data, a novel BC signal was localized to an 8.6-kb region of 17q25.3 by 4 SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and stayed statistically significant after several 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).
• Findings suggested that 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).
• The strongest signals for hormone receptor, luminal vs basal-like, and HER2 enrichment status were miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1, respectively.
• Results demonstrated that for validation and meta-analysis a second phase of genotyping (1,397 BC cases, 2,418 controls) that included 2 SNPs in the 8.6-kb region was used.
• Data demonstrated that while validation of neither rs4969239 nor rs9913477 was done, 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).