5′ Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints
Authors:
- Sandrine M. CaputoSCSandrine M. Caputo
- Dominique TellyDTDominique Telly
- Adrien BriauxABAdrien Briaux
- Julie SesenJSJulie Sesen
- Maurizio CeppiMCMaurizio Ceppi
- Françoise BonnetFBFrançoise Bonnet
- Violaine BourdonVBViolaine Bourdon
- Florence CouletFCFlorence Coulet
- Laurent CasteraLCLaurent Castera
- Capucine DelnatteCDCapucine Delnatte
- Agnès HardouinAHAgnès Hardouin
- Sylvie MazoyerSMSylvie Mazoyer
Open Access
Abstract
Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.Keywords
Funding Information
- Institut National Du Cancer (2013-1-BCB-01-ICH-1)
- GENETICANCER (-)
- Cercle de l’Olympe (-)
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