Familial breast cancer and DNA repair genes: insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Elodie Girard, Séverine Eon-Marchais, Robert Olaso, Anne Laure Renault, Francesca Damiola, Marie Gabrielle Dondon, Laure Barjhoux, Didier Goidin, Vincent Meyer, Dorothée Le Gal, Juana Beauvallet, Noura Mebirouk, Christine Lonjou, Juliette Coignard, Morgane Marcou, Eve Cavaciuti, Céline Baulard, Marie Thérèse Bihoreau, Odile Cohen-Haguenauer, Dominique LerouxClotilde Penet, Sandra Fert-Ferrer, Chrystelle Colas, Thierry Frebourg, François Eisinger, Claude Adenis, Anne Fajac, Laurence Gladieff, Julie Tinat, Anne Floquet, Jean Chiesa, Sophie Giraud, Isabelle Mortemousque, Florent Soubrier, Séverine Audebert-Bellanger, Jean Marc Limacher, Christine Lasset, Sophie Lejeune-Dumoulin, Hélène Dreyfus, Yves Jean Bignon, Michel Longy, Pascal Pujol, Laurence Venat-Bouvet, Valérie Bonadona, Pascaline Berthet, Elisabeth Luporsi, Christine M. Maugard, Catherine Noguès, Capucine Delnatte, Jean Pierre Fricker, Paul Gesta, Laurence Faivre, Alain Lortholary, Bruno Buecher, Olivier Caron, Marion Gauthier-Villars, Isabelle Coupier, Nicolas Servant, Anne Boland, Sylvie Mazoyer, Jean François Deleuze, Dominique Stoppa-Lyonnet, Nadine Andrieu, Fabienne Lesueur

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31 Citations (Scopus)


Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of this study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analysed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N=1,207), and general population controls (N=1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF=17.4 vs. ORMV=1.6; PHet=0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.
Original languageEnglish
Pages (from-to)1962-1974
Number of pages13
JournalInternational Journal of Cancer
Issue number8
Publication statusPublished - 15 Apr 2019
Externally publishedYes


  • breast cancer
  • case–control study
  • exome sequencing
  • multigene panel testing
  • variant

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