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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 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 Sophie Giraud 22 Isabelle Mortemousque 23 Florent Soubrier 24 Séverine Audebert‐bellanger 25 Jean‐marc Limacher 26 Christine Lasset 27 Sophie Lejeune‐dumoulin 28 Hélène Dreyfus 29 Yves‐jean Bignon 30 Michel Longy 31 Pascal Pujol 32, 33 Laurence Venat‐bouvet 34 Valerie Bonadona 35 Pascaline Berthet 36 Elisabeth Luporsi 37 Christine Maugard 38 Catherine Noguès 39 Capucine Delnatte 40 Jean‐pierre Fricker 41 Paul Gesta 42 Laurence Faivre 43 Alain Lortholary 44 Bruno Buecher 45 Olivier Caron 46 Marion Gauthier‐villars 47 Isabelle Coupier 48 Nicolas Servant 1, 2 Anne Boland 3 Sylvie Mazoyer 49 Jean‐françois Deleuze 3 Dominique Stoppa‐lyonnet 13, 50 Nadine Andrieu 1, 2 Fabienne Lesueur 1, 2, *
* Corresponding author
35 Biostatistiques santé
Département biostatistiques et modélisation pour la santé et l'environnement [LBBE]
46 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 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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