5′ Region Large Genomic Rearrangements in the <em>BRCA1</em> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints
Background: Large genomic rearrangements (LGR) in <i>BRCA1</i> 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...
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MDPI AG
2021-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/13/3171 |
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| 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 |
| author_facet | 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 |
| author_sort | Sandrine M. Caputo |
| collection | DOAJ |
| description | Background: Large genomic rearrangements (LGR) in <i>BRCA1</i> 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 <i>BRCA1</i>, 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 <i>BRCA1</i> 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. |
| first_indexed | 2024-03-10T10:03:34Z |
| format | Article |
| id | doaj.art-69f54c8c0ec1496b9442ff90346e2b46 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T10:03:34Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-69f54c8c0ec1496b9442ff90346e2b462023-11-22T01:42:30ZengMDPI AGCancers2072-66942021-06-011313317110.3390/cancers131331715′ Region Large Genomic Rearrangements in the <em>BRCA1</em> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent BreakpointsSandrine M. Caputo0Dominique Telly1Adrien Briaux2Julie Sesen3Maurizio Ceppi4Françoise Bonnet5Violaine Bourdon6Florence Coulet7Laurent Castera8Capucine Delnatte9Agnès Hardouin10Sylvie Mazoyer11Inès Schultz12Nicolas Sevenet13Nancy Uhrhammer14Céline Bonnet15Anne-Françoise Tilkin-Mariamé16Claude Houdayer17Virginie Moncoutier18Catherine Andrieu19French COVAR Group CollaboratorsIvan Bièche20Marc-Henri Stern21Dominique Stoppa-Lyonnet22Rosette Lidereau23Christine Toulas24Etienne Rouleau25Department of Genetics, Institut Curie, F-75248 Paris, FranceLaboratoire d’Oncogénétique, Institut Claudius Regaud, IUCT-O, F-31059 Toulouse, FranceDepartment of Genetics, Institut Curie, F-75248 Paris, FranceDepartment of Neurosurgery, Boston Children’s Hospital, Boston, MA 02115, USARoche Innovation Center Basel (RICB), Roche Pharma Research and Early Development, CH-4052 Basel, SwitzerlandLaboratoire de Génétique Constitutionnelle et INSERM U916 VINCO, Institut Bergonié, CEDEX, F-33076 Bordeaux, FranceLaboratoire d’Oncogénétique Moléculaire, Département de Biologie du Cancer, Institut Paoli-Calmettes, F-13273 Marseille, FranceDepartment of Genetics, Pitié-Salpêtriere Hospital, Assistance Publique-Hopitaux de Paris, Sorbonne University, F-75013 Paris, FranceLaboratoire de Biologie et de Génétique du Cancer, CLCC François Baclesse, INSERM 1079 Centre Normand de Génomique et de Médecine Personnalisée, F-14076 Caen, FranceService de Génétique Médicale, Unité de Génétique Moléculaire, CHU Nantes, F-44093 Nantes, FranceLaboratoire de Biologie et de Génétique du Cancer, CLCC François Baclesse, INSERM 1079 Centre Normand de Génomique et de Médecine Personnalisée, F-14076 Caen, FranceCentre de Recherche en Neurosciences de Lyon, INSERM, U1028, CNRS, UMR5292, Université de Lyon, F-69008 Lyon, FranceCentre Paul Strauss, Laboratoire de Biologie Tumorale—Oncogénétique, F-67000 Strasbourg, FranceLaboratoire de Génétique Constitutionnelle et INSERM U916 VINCO, Institut Bergonié, CEDEX, F-33076 Bordeaux, FranceBiologie Clinique et Oncologique, Biologie Moléculaire—Centre Jean Perrin, F-63000 Clermont-Ferrand, FranceInstitut de Cancérologie, 6 Avenue de Bourgogne, F-54519 Vandœuvre-lès-Nancy, FranceCancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1037, F-31000 Toulouse, FranceInserm U1245, UNIROUEN, Normandie University, Normandy Centre for Genomic and Personalized Medicine, F-76183 Rouen, FranceDepartment of Genetics, Institut Curie, F-75248 Paris, FranceDepartment of Genetics, Institut Curie, F-75248 Paris, FranceDepartment of Genetics, Institut Curie, F-75248 Paris, FranceDepartment of Genetics, Institut Curie, F-75248 Paris, FranceDepartment of Genetics, Institut Curie, F-75248 Paris, FranceDepartment of Genetics, Institut Curie, F-75248 Paris, FranceLaboratoire d’Oncogénétique, Institut Claudius Regaud, IUCT-O, F-31059 Toulouse, FranceDepartment of Biology, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, FranceBackground: Large genomic rearrangements (LGR) in <i>BRCA1</i> 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 <i>BRCA1</i>, 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 <i>BRCA1</i> 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.https://www.mdpi.com/2072-6694/13/13/3171large genomic rearrangement<i>BRCA1</i> genelarge duplicationtriplicationvariant of unknown significance |
| spellingShingle | 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 5′ Region Large Genomic Rearrangements in the <em>BRCA1</em> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints Cancers large genomic rearrangement <i>BRCA1</i> gene large duplication triplication variant of unknown significance |
| title | 5′ Region Large Genomic Rearrangements in the <em>BRCA1</em> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints |
| title_full | 5′ Region Large Genomic Rearrangements in the <em>BRCA1</em> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints |
| title_fullStr | 5′ Region Large Genomic Rearrangements in the <em>BRCA1</em> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints |
| title_full_unstemmed | 5′ Region Large Genomic Rearrangements in the <em>BRCA1</em> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints |
| title_short | 5′ Region Large Genomic Rearrangements in the <em>BRCA1</em> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints |
| title_sort | 5 region large genomic rearrangements in the em brca1 em gene in french families identification of a tandem triplication and nine distinct deletions with five recurrent breakpoints |
| topic | large genomic rearrangement <i>BRCA1</i> gene large duplication triplication variant of unknown significance |
| url | https://www.mdpi.com/2072-6694/13/13/3171 |
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