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; Séverine Eon‐marchais; Robert Olaso; Anne‐laure Renault; Francesca Damiola; Marie‐gabrielle Dondon; Laure Barjhoux; Didier Goidin; Vincent Meyer; Dorothée Le Gal; Juana Beauvallet; Noura Mebirouk; Christine Lonjou; Juliette Coignard; Morgane Marcou; Eve Cavaciuti; Céline Baulard; Marie‐thérèse Bihoreau; Odile Cohen‐haguenauer; Dominique Leroux; Clotilde Penet; Sandra Fert‐ferrer; Chrystelle Colas; Thierry Frébourg; Francois Eisinger; Claude Adenis; Anne Fajac; Laurence Gladieff; Julie Tinat; Anne Floquet; Jean Chiesa; Sophie Giraud; Isabelle Mortemousque; Florent Soubrier; Séverine Audebert‐bellanger; Jean‐marc Limacher; Christine Lasset; Sophie Lejeune‐dumoulin; Hélène Dreyfus; Yves‐jean Bignon; Michel Longy; Pascal Pujol; Laurence Venat‐bouvet; Valerie Bonadona; Pascaline Berthet; Elisabeth Luporsi; Christine Maugard; Catherine Noguès; Capucine Delnatte; Jean‐pierre Fricker; Paul Gesta; Laurence Faivre; Alain Lortholary; Bruno Buecher; Olivier Caron; Marion Gauthier‐villars; Isabelle Coupier; Nicolas Servant; Anne Boland; Sylvie Mazoyer; Jean‐françois Deleuze; Dominique Stoppa‐lyonnet; Nadine Andrieu; Fabienne Lesueur

doi:10.1002/ijc.31921

Journal articles

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

1 PSL - Université Paris sciences et lettres

2 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe

3 CNG - Centre National de Génotypage

4 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon

5 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents

6 Life Sciences and Diagnostics Group [Les Ulis, France]

7 I3M - Laboratoire Information, Milieux, Médias, Médiations - EA 3820

8 Hôpital Saint-Louis

9 TAMCIC - Traitement Algorithmique et Matériel de la Communication, de l'Information et de la Connaissance

10 CRLCC Jean Godinot

11 C.H.de Chambéry - Centre Hospitalier de Chambéry

12 CR Saint-Antoine - Centre de Recherche Saint-Antoine

13 Unité de Pharmacogénomique - Département de Génétique [Institut Curie, Paris]

14 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques

15 SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD - Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale

16 UNICANCER/Lille - Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille]

17 CHU Tenon [APHP]

18 Institut Claudius Regaud

19 Service de génétique [Rouen]

20 Département d'oncologie médicale

21 Laboratoire de Cytogénétique

22 Hôpital Edouard Herriot [CHU - HCL]

23 Service de génétique [Tours]

24 Génétique épidémiologique et moléculaire des pathologies cardiovasculaires

25 Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest]

26 Hôpital pasteur [Colmar]

27 LBBE - Laboratoire de Biométrie et Biologie Evolutive - UMR 5558

28 Hôpital Jeanne de Flandres

29 Institut Sainte Catherine [Avignon]

30 IMoST - Imagerie Moléculaire et Stratégies Théranostiques

31 Département de pathologie

32 Hôpital Arnaud de Villeneuve [CHRU Montpellier]

33 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier

34 Hôpital Dupuytren [CHU Limoges]

35 Biostatistiques santé

Département biostatistiques et modélisation pour la santé et l'environnement [LBBE]

36 Consultation d'Oncogénétique

37 CAV - Centre Alexis Vautrin

38 Laboratoire de Diagnostic Génétique [CHU Strasbourg]

39 Laboratoire d'Oncogénétique

40 CRLCC René Gauducheau

41 UNICANCER Centre Paul Strauss - Service d'Oncologie Médicale [Strasbourg]

42 CH Georges Renon Niort - Centre Hospitalier Georges Renon [Niort]

43 GAD - Génétique des Anomalies du Développement

44 CCS - Centre Catherine-de-Sienne [Nantes]

45 Service de Génétique Oncologique

46 Onco-génétique

Département de médecine oncologique [Gustave Roussy]

47 Institut Curie [Paris]

48 Unité d'Oncogénétique

49 CRNL - Centre de recherche en neurosciences de Lyon

50 U830 - Unité de génétique et biologie des cancers

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.

Keywords : multigene panel testing breast cancer case-control study exome sequencing variant

Document type :

Journal articles

Domain :

Life Sciences [q-bio]

Life Sciences [q-bio] / Genetics

Life Sciences [q-bio] / Genetics / Human genetics

Life Sciences [q-bio] / Santé publique et épidémiologie

Life Sciences [q-bio] / Cancer

Complete list of metadatas

Cited literature [55 references] Display Hide Download

https://www.hal.inserm.fr/inserm-02438452
Contributor : Nadine Andrieu <>
Submitted on : Tuesday, January 14, 2020 - 11:21:33 AM
Last modification on : Wednesday, February 24, 2021 - 11:26:04 AM
Long-term archiving on: : Wednesday, April 15, 2020 - 5:59:46 PM

Girard_et_al-2019-Internationa...

Publication funded by an institution

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

File

Identifiers

Collections

Citation

Export

Metrics

744

1053

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

File

Identifiers

Collections

Citation

Export

Share

Metrics

744

1053