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Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer

Sandrine Caputo 1 Mélanie Léoné 2 Francesca Damiola 3 Asa Ehlen 4 Aura Carreira 4 Pascaline Gaidrat 5 Alexandra Martins 5 Rita Brandão Ana Peixoto 6 Ana Vega 7 Claude Houdayer 8, 1 Capucine Delnatte 9 Myriam Bronner Danièle Muller Laurent Castera 10, 11 Marine Guillaud-Bataille 12 Inge Søkilde Nancy Uhrhammer 13, 14 Sophie Demontety Hélène Tubeuf 5 Gaïa Castelain 5 Uffe Birk Jensen 15 Ambre Petitalot 16 Sophie Krieger 10, 11 Cédrick Lefol 1 Virginie Moncoutier 1 Nadia Boutry-Kryza 17 Henriette Roed Nielsen Olga Sinilnikova 18 Dominique Stoppa-Lyonnet 16 Amanda Spurdle 19 Manuel Teixeira Florence Coulet 20 Mads Thomassen 15 Etienne Rouleau 1
1 Institut Curie [Paris]
2 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
3 CGPhiMC - Centre de génétique et de physiologie moléculaire et cellulaire
4 Stress génotoxiques et cancer
5 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
6 Department of Genetics
7 Genomic Medicine Group
8 UPD5 - Université Paris Descartes - Paris 5
9 Centre René Gauducheau
10 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
11 GMFC - Génétique du cancer et des maladies neuropsychiatriques
12 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
13 UNICANCER/CJP - Centre Jean Perrin [Clermont-Ferrand]
14 IMoST - Imagerie Moléculaire et Stratégies Théranostiques
15 Department of Clinical Genetics
16 U830 - Unité de génétique et biologie des cancers
17 Laboratoire de Génétique
18 Equipe 6
UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
19 Division of Genetics and Population Health
20 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition
Abstract : Germline pathogenic variants in the BRCA2 gene are associated with a cumulative high risk of breast/ovarian cancer. Several BRCA2 variants result in complete loss of the exon-3 at the transcript level. The pathogenicity of these variants and the functional impact of loss of exon 3 have yet to be established. As a collaboration of the COVAR clinical trial group (France), and the ENIGMA consortium for investigating breast cancer gene variants, this study evaluated 8 BRCA2 variants resulting in complete deletion of exon 3. Clinical information for 39 families was gathered from Portugal, France, Denmark and Sweden. Multifactorial likelihood analyses were conducted using information from 293 patients, for 7 out of the 8 variants (including 6 intronic). For all variants combined the likelihood ratio in favor of causality was 4.39*1025. These results provide convincing evidence for the pathogenicity of all examined variants that lead to a total exon 3 skipping, and suggest that other variants that result in complete loss of exon 3 at the molecular level could be associated with a high risk of cancer comparable to that associated with classical pathogenic variants in BRCA1 or BRCA2 gene. In addition, our functional study shows, for the first time, that deletion of exon 3 impairs the ability of cells to survive upon Mitomycin-C treatment, supporting lack of function for the altered BRCA2 protein in these cells. Finally, this study demonstrates that any variant leading to expression of only BRCA2 delta-exon 3 will be associated with an increased risk of breast and ovarian cancer.
Keywords : RNA splicing defects splice donor site PALB2 variants BRCA2 exon3
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USPC | UNIV-LYON1 | PRES_CLERMONT | IMOST | CRCL | UNIROUEN | ICAN | SU-MEDECINE | SU-SCIENCES | IBPS | UNIV-PARIS5 | FNCLCC | HEH | SORBONNE-UNIVERSITE | COMUE-NORMANDIE | CNRS | HCL | CURIE | BACLESSE | ICO | GAUDUCHEAU | CGPHIMC | ACL-SVSAE | INSERM | GPMCND | UDL | UNIV-PARIS | UP-SANTE | PSL | SU-TI

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Sandrine Caputo, Mélanie Léoné, Francesca Damiola, Asa Ehlen, Aura Carreira, et al.. Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer. Oncotarget, Impact journals, 2018, 9 (9), pp.17334-17348. ⟨10.18632/oncotarget.24671⟩. ⟨hal-01928011⟩

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