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 Séverine Eon-Marchais 2 François Olaso Anne Renault Francesca Damiola 3 Marie-Gabrielle Dondon 4 Laure Barjhoux 5 Didier Goidin François Meyer Dorothée Le Gal 2 Juana Beauvallet 2 Noura Mebirouk 2 Christine Lonjou 6 Julie Coignard Morgane Marcou 2 Eve Cavaciuti 2 François Baulard 7 François Bihoreau Odile Cohen-Haguenauer 8 Dominique Leroux 9 Jean Penet Sandra Fert-Ferrer Chrystelle Colas 10 Thierry Frebourg 11 François Eisinger 12 Claude Adenis 13 Anne Fajac 14 Laurence Gladieff 15 Julie Tinat 11 Anne Floquet 16 Jean Chiesa 17 Sophie Giraud 18 Isabelle Mortemousque 19 Florent Soubrier 20 Séverine Audebert-Bellanger 21 Jean-Marc Limacher 22 Christine Lasset 23 Sophie Lejeune-Dumoulin 24 Catherine Dreyfus Yves-Jean Bignon 25, 26 Michel Longy 27 Pascal Pujol 28 Laurence Venat-Bouvet 29 Valérie Bonadona 30 Pascaline Berthet 31 Elisabeth Luporsi 32 Christine Maugard 33 Catherine Noguès 34 Capucine Delnatte 35 Paul Fricker Paul Gesta 36 Laurence Faivre 37, 38, 39 Alain Lortholary 40 Bruno Buecher 41 Olivier Caron 42 Marion Gauthier-Villars 43 Isabelle Coupier 44 Nicolas Servant 2 Anne Boland 45 Sylvie Mazoyer 46 Jean-François Deleuze 45 Dominique Stoppa-Lyonnet 47, 48 Nadine Andrieu 49 Fabienne Lesueur 50
5 E06
CRCL - Centre de Recherche en Cancérologie de Lyon, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
23 Biostatistiques santé
Département biostatistiques et modélisation pour la santé et l'environnement [LBBE]
46 Equipe 6
CRCL - Centre de Recherche en Cancérologie de Lyon
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.What’s new?Pathogenic variants in BRCA1 and BRCA2 only explain the genetic cause of about 10% of hereditary breast and ovarian cancer families, and the clinical usefulness of testing other genes following the recent introduction of cost-effective multigene panel sequencing in diagnostics laboratories remains questionable. This large case-control study describes genetic variation in 113 DNA repair genes and specifies breast cancer relative risks associated with rare deleteriouspredicted variants in PALB2, ATM, and CHEK2. Importantly, different types of variants within the same gene can lead to different risk estimates. The results may help improve risk prediction models and define gene-specific consensus management guidelines.
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https://hal.archives-ouvertes.fr/hal-01926987
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Submitted on : Monday, November 19, 2018 - 3:27:41 PM
Last modification on : Thursday, October 3, 2019 - 1:22:52 AM

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Elodie Girard, Séverine Eon-Marchais, François Olaso, Anne 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⟩. ⟨hal-01926987⟩

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