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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.

Author information

1
Department of Oncology, Center for Translational Oncology, Cancer Institute of the State of São Paulo - ICESP, São Paulo, Brazil.
2
Service de Génétique, Institut Curie, Paris, France.
3
A.C.Camargo Cancer Center, São Paulo, Brazil.
4
Laboratoire de Biologie et de Génétique du Cancer, CLCC François Baclesse, INSERM 1079 Centre Normand de Génomique et de MédecinePersonnalisée, Caen, France.
5
Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.
6
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
7
Université Paris Descartes, Paris, France.
8
Service de Génétique, Institut Curie, Paris, France. francois.lallemand@curie.fr.
9
Gustave Roussy, Villejuif, France. Etienne.rouleau@gustaveroussy.fr.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

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

PMID:
29236234
DOI:
10.1007/s10549-017-4602-0

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