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
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.
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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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