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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

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Department of Genetics, Institut Curie, F-75248 Paris, France
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Institut Curie, PSL Research University, F-75005 Paris, France
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Laboratoire d’Oncogénétique, Institut Claudius Regaud, IUCT-O, F-31059 Toulouse, France
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Department of Neurosurgery, Boston Children’s Hospital, Boston, MA 02115, USA
5
Roche Innovation Center Basel (RICB), Roche Pharma Research and Early Development, CH-4052 Basel, Switzerland
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Laboratoire de Génétique Constitutionnelle et INSERM U916 VINCO, Institut Bergonié, CEDEX, F-33076 Bordeaux, France
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Laboratoire d’Oncogénétique Moléculaire, Département de Biologie du Cancer, Institut Paoli-Calmettes, F-13273 Marseille, France
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Department of Genetics, Pitié-Salpêtriere Hospital, Assistance Publique-Hopitaux de Paris, Sorbonne University, F-75013 Paris, France
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Laboratoire de Biologie et de Génétique du Cancer, CLCC François Baclesse, INSERM 1079 Centre Normand de Génomique et de Médecine Personnalisée, F-14076 Caen, France
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Service de Génétique Médicale, Unité de Génétique Moléculaire, CHU Nantes, F-44093 Nantes, France
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Centre de Recherche en Neurosciences de Lyon, INSERM, U1028, CNRS, UMR5292, Université de Lyon, F-69008 Lyon, France
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Centre Paul Strauss, Laboratoire de Biologie Tumorale—Oncogénétique, F-67000 Strasbourg, France
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Biologie Clinique et Oncologique, Biologie Moléculaire—Centre Jean Perrin, F-63000 Clermont-Ferrand, France
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Institut de Cancérologie, 6 Avenue de Bourgogne, F-54519 Vandœuvre-lès-Nancy, France
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Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, F-31000 Toulouse, France
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Inserm U1245, UNIROUEN, Normandie University, Normandy Centre for Genomic and Personalized Medicine, F-76183 Rouen, France
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Normandy Centre for Genomic and 41 Personalized Medicine, Department of Genetics, University Hospital, F-76183 Rouen, France
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Faculty of Pharmaceutical and Biological Sciences, University of Paris, F-75006 Paris, France
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Institut Curie, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), PSL Research University, F-75005 Paris, France
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Faculty of Medicine, University of Paris, F-75005 Paris, France
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Department of Biology, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France
*
Authors to whom correspondence should be addressed.
Membership of the French COVAR Group Collaborators is provided in the Acknowledgments.
Academic Editors: Eladio A. Velasco, Maaike P. G. Vreeswijk and Miguel De la Hoya
Cancers 2021, 13(13), 3171; https://doi.org/10.3390/cancers13133171
Received: 30 April 2021 / Revised: 11 June 2021 / Accepted: 17 June 2021 / Published: 25 June 2021
(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)
Large genomic rearrangements in BRCA1 consisting of deletions/duplications of one or several exons are complex events, often occurring in the 5′ region. We characterized 10 events in 20 families: one large triplication classified as benign and nine large deletions classified as pathogenic. The breakpoint localization will certainly help to further understand the chromatin structure in regions sensitive to rearrangement.
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. View Full-Text
Keywords: large genomic rearrangement; BRCA1 gene; large duplication; triplication; variant of unknown significance large genomic rearrangement; BRCA1 gene; large duplication; triplication; variant of unknown significance
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Figure 1

MDPI and ACS Style

Caputo, S.M.; Telly, D.; Briaux, A.; Sesen, J.; Ceppi, M.; Bonnet, F.; Bourdon, V.; Coulet, F.; Castera, L.; Delnatte, C.; Hardouin, A.; Mazoyer, S.; Schultz, I.; Sevenet, N.; Uhrhammer, N.; Bonnet, C.; Tilkin-Mariamé, A.-F.; Houdayer, C.; Moncoutier, V.; Andrieu, C.; French COVAR Group Collaborators; Bièche, I.; Stern, M.-H.; Stoppa-Lyonnet, D.; Lidereau, R.; Toulas, C.; Rouleau, E. 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. Cancers 2021, 13, 3171. https://doi.org/10.3390/cancers13133171

AMA Style

Caputo SM, Telly D, Briaux A, Sesen J, Ceppi M, Bonnet F, Bourdon V, Coulet F, Castera L, Delnatte C, Hardouin A, Mazoyer S, Schultz I, Sevenet N, Uhrhammer N, Bonnet C, Tilkin-Mariamé A-F, Houdayer C, Moncoutier V, Andrieu C, French COVAR Group Collaborators, Bièche I, Stern M-H, Stoppa-Lyonnet D, Lidereau R, Toulas C, Rouleau E. 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. Cancers. 2021; 13(13):3171. https://doi.org/10.3390/cancers13133171

Chicago/Turabian Style

Caputo, Sandrine M., 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, and Etienne Rouleau. 2021. "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" Cancers 13, no. 13: 3171. https://doi.org/10.3390/cancers13133171

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