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Open Access Highly Accessed Research article

A germline mutation in the BRCA1 3’UTR predicts Stage IV breast cancer

Jemima J Dorairaj1, David W Salzman2, Deirdre Wall34, Tiffany Rounds5, Carina Preskill2, Catherine AW Sullivan6, Robert Lindner7, Catherine Curran1, Kim Lezon-Geyda6, Terri McVeigh1, Lyndsay Harris6, John Newell34, Michael J Kerin1, Marie Wood5, Nicola Miller1 and Joanne B Weidhaas2*

Author Affiliations

1 Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland

2 Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA

3 HRB Clinical Research Facility, National University of Ireland, Galway, Ireland

4 School of Mathematics, Statistics and Applied Mathematics, National University of Ireland, Galway, Ireland

5 Department of Medicine, University of Vermont, Burlington, VT 05405, USA

6 Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA

7 Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany

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BMC Cancer 2014, 14:421  doi:10.1186/1471-2407-14-421

Published: 10 June 2014



A germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer.


The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont.


Luciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the Vermont cohort.


A variant in the 3’UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.

BRCA1-3’UTR-variant; Mutation; Breast cancer; Stage IV breast cancer; Metastatic breast cancer; Biomarker; Diagnostic marker