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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.


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.

SUBMITTER: Girard E 

PROVIDER: S-EPMC6587727 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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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.

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

International journal of cancer 20181113 8


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  ...[more]

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