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Breast Cancer Research
Published in: Breast Cancer Research 1/2018

Open Access 01-12-2018 | Research article

A survey of microRNA single nucleotide polymorphisms identifies novel breast cancer susceptibility loci in a case-control, population-based study of African-American women

Authors: Jeannette T. Bensen, Mariaelisa Graff, Kristin L. Young, Praveen Sethupathy, Joel Parker, Chad V. Pecot, Kevin Currin, Stephen A. Haddad, Edward A. Ruiz-Narváez, Christopher A. Haiman, Chi-Chen Hong, Lara E. Sucheston-Campbell, Qianqian Zhu, Song Liu, Song Yao, Elisa V. Bandera, Lynn Rosenberg, Kathryn L. Lunetta, Christine B. Ambrosone, Julie R. Palmer, Melissa A. Troester, Andrew F. Olshan

Published in: Breast Cancer Research | Issue 1/2018

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Abstract

Background

MicroRNAs (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.

Methods

Under 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.

Results

A 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).

Conclusion

Germline 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.
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Metadata
Title
A survey of microRNA single nucleotide polymorphisms identifies novel breast cancer susceptibility loci in a case-control, population-based study of African-American women
Authors
Jeannette T. Bensen
Mariaelisa Graff
Kristin L. Young
Praveen Sethupathy
Joel Parker
Chad V. Pecot
Kevin Currin
Stephen A. Haddad
Edward A. Ruiz-Narváez
Christopher A. Haiman
Chi-Chen Hong
Lara E. Sucheston-Campbell
Qianqian Zhu
Song Liu
Song Yao
Elisa V. Bandera
Lynn Rosenberg
Kathryn L. Lunetta
Christine B. Ambrosone
Julie R. Palmer
Melissa A. Troester
Andrew F. Olshan
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2018
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-018-0964-4

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