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Breast Cancer Res Treat. 2018 Apr;168(2):311-325. doi: 10.1007/s10549-017-4602-0. Epub 2017 Dec 13.

Assessment of the functional impact of germline BRCA1/2 variants located in non-coding regions in families with breast and/or ovarian cancer predisposition.

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Department of Oncology, Center for Translational Oncology, Cancer Institute of the State of São Paulo - ICESP, São Paulo, Brazil.
Service de Génétique, Institut Curie, Paris, France.
A.C.Camargo Cancer Center, São Paulo, Brazil.
Laboratoire de Biologie et de Génétique du Cancer, CLCC François Baclesse, INSERM 1079 Centre Normand de Génomique et de MédecinePersonnalisée, Caen, France.
Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
Université Paris Descartes, Paris, France.
Service de Génétique, Institut Curie, Paris, France.
Gustave Roussy, Villejuif, France.



The molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants.


Four BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay.


We identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C > T) and one BRCA2 promoter variants (c.-296C > T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A > G and c.4186-2022C > T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities.


In this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants.


BRCA1/2 non-coding variants; BRCA1/2 transcription regulation; Breast and/or ovarian cancer risk; Hereditary breast and/or ovarian cancer (HBOC)

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