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

Girard E1,2,3,4, Eon-Marchais S1,2,3,4, Olaso R5, Renault AL1,2,3,4, Damiola F6, Dondon MG1,2,3,4, Barjhoux L6, Goidin D7, Meyer V5, Le Gal D1,2,3,4, Beauvallet J1,2,3,4, Mebirouk N1,2,3,4, Lonjou C1,2,3,4, Coignard J1,2,3,4,8, Marcou M1,2,3,4, Cavaciuti E1,2,3,4, Baulard C5, Bihoreau MT5, Cohen-Haguenauer O9, Leroux D10, Penet C11, Fert-Ferrer S12, Colas C13,14, Frebourg T15, Eisinger F16, Adenis C17, Fajac A18, Gladieff L19, Tinat J15, Floquet A20, Chiesa J21, Giraud S22, Mortemousque I23, Soubrier F24, Audebert-Bellanger S25, Limacher JM26, Lasset C27, Lejeune-Dumoulin S28, Dreyfus H29, Bignon YJ30, Longy M20, Pujol P31, Venat-Bouvet L32, Bonadona V27, Berthet P33, Luporsi E34, Maugard CM35, Noguès C16, Delnatte C36, Fricker JP37, Gesta P38, Faivre L39, Lortholary A40, Buecher B14, Caron O41, Gauthier-Villars M14, Coupier I31, Servant N1,2,3,4, Boland A5, Mazoyer S42, Deleuze JF5, Stoppa-Lyonnet D14,43,44, Andrieu N1,2,3,4, Lesueur F1,2,3,4.

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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 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. This article is protected by copyright. All rights reserved.