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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 1, 2 Séverine Eon‐marchais 1, 2 Robert E Olaso 3 Anne‐laure Renault 1, 2 Francesca Damiola 4 Marie‐gabrielle Dondon 1, 2 Laure Barjhoux 5 Didier Goidin 6 Vincent Meyer 7 Dorothée Le Gal 2, 1 Juana Beauvallet 2, 1 Noura Mebirouk 2, 1 Christine Lonjou 2, 1 Juliette Coignard 2, 1 Morgane Marcou 2, 1 Eve Cavaciuti 2, 1 Céline Baulard 3 Marie‐thérèse Bihoreau 3 Odile Cohen‐haguenauer 8 Dominique Leroux 9 Clotilde Penet 10 Sandra Fert‐ferrer 11 Chrystelle Colas 12, 13 Thierry Frébourg 14 Francois Eisinger 15 Claude Adenis 16 Anne Fajac 17 Laurence Gladieff 18 Julie Tinat 19 Anne Floquet 20 Jean Chiesa 21, 22 Sophie Giraud 23 Isabelle Mortemousque 24 Florent Soubrier 25 Séverine Audebert‐bellanger 26 Jean‐marc Limacher 27 Christine C. Lasset 28 Sophie Lejeune‐dumoulin 29 Hélène Dreyfus 30 Yves‐jean Bignon 31 Michel Longy 32 Pascal Pujol 33, 34 Laurence Venat‐bouvet 35 Valerie V. Bonadona 36 Pascaline Berthet 37 Elisabeth Luporsi 38 Christine Maugard 39 Catherine Noguès 40 Capucine Delnatte 41 Jean‐pierre Fricker 42 Paul Gesta 43 Laurence Faivre 44 Alain Lortholary 45 Bruno Buecher 46 Olivier Caron 47 Marion Gauthier‐villars 48 Isabelle Coupier 49 Nicolas Servant 1, 2 Anne Boland 3 Sylvie Mazoyer 50 Jean‐françois Deleuze 3 Dominique Stoppa‐lyonnet 13, 51 Nadine N. Andrieu 1, 2 Fabienne Lesueur 1, 2, * 
* Corresponding author
36 Biostatistiques santé
Département biostatistiques et modélisation pour la santé et l'environnement [LBBE]
47 Onco-génétique
Département de médecine oncologique [Gustave Roussy]
Abstract : 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 our 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 analyzed 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; p Het = 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.
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Elodie Girard, Séverine Eon‐marchais, Robert E Olaso, Anne‐laure Renault, Francesca Damiola, et al.. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. International Journal of Cancer, Wiley, 2019, 144 (8), pp.1962-1974. ⟨10.1002/ijc.31921⟩. ⟨inserm-02438452⟩



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