학술논문
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
Document Type
article
Author
Sandrine M. Caputo; Dominique Telly; Adrien Briaux; Julie Sesen; Maurizio Ceppi; Françoise Bonnet; Violaine Bourdon; Florence Coulet; Laurent Castera; Capucine Delnatte; Agnès Hardouin; Sylvie Mazoyer; Inès Schultz; Nicolas Sevenet; Nancy Uhrhammer; Céline Bonnet; Anne-Françoise Tilkin-Mariamé; Claude Houdayer; Virginie Moncoutier; Catherine Andrieu; French COVAR Group Collaborators; Ivan Bièche; Marc-Henri Stern; Dominique Stoppa-Lyonnet; Rosette Lidereau; Christine Toulas; Etienne Rouleau
Source
Cancers, Vol 13, Iss 13, p 3171 (2021)
Subject
Language
English
ISSN
2072-6694
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.