TY - JOUR
T1 - Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer
AU - Caputo, Sandrine M
AU - Léone, Mélanie
AU - Damiola, Francesca
AU - Ehlen, Asa
AU - Carreira, Aura
AU - Gaidrat, Pascaline
AU - Martins, Alexandra
AU - Brandão, Rita D
AU - Peixoto, Ana
AU - Vega, Ana
AU - Houdayer, Claude
AU - Delnatte, Capucine
AU - Bronner, Myriam
AU - Muller, Danièle
AU - Castera, Laurent
AU - Guillaud-Bataille, Marine
AU - Pedersen, Inge Søkilde
AU - Uhrhammer, Nancy
AU - Demontety, Sophie
AU - Tubeuf, Hélène
AU - Castelain, Gaïa
AU - French COVAR group collaborators
AU - Jensen, Uffe Birk
AU - Petitalot, Ambre
AU - Krieger, Sophie
AU - Lefol, Cédrick
AU - Moncoutier, Virginie
AU - Boutry-Kryza, Nadia
AU - Nielsen, Henriette Roed
AU - Sinilnikova, Olga
AU - Stoppa-Lyonnet, Dominique
AU - Spurdle, Amanda B
AU - Teixeira, Manuel R
AU - Coulet, Florence
AU - Thomassen, Mads
AU - Rouleau, Etienne
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
KW - BRCA2 exon3
KW - PALB2
KW - RNA splicing defects
KW - Splice donor site
KW - Variants
UR - http://www.scopus.com/inward/record.url?scp=85044827158&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24671
DO - 10.18632/oncotarget.24671
M3 - Journal article
C2 - 29707112
SN - 1949-2553
VL - 9
SP - 17334
EP - 17348
JO - Oncotarget
JF - Oncotarget
IS - 25
ER -