Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

Mariette Renaux-Petel; Françoise Charbonnier; Jean-Christophe Théry; Pierre Fermey; Gwendoline Lienard; Jacqueline Bou; Sophie Coutant; Myriam Vezain; Edwige Kasper; Steeve Fourneaux; Sandrine Manase; Maud Blanluet; Bruno Leheup; Ludovic Mansuy; Jacqueline Champigneulle; Céline Chappé; Michel Longy; Nicolas Sévenet; Brigitte Bressac-de Paillerets; Léa Guerrini-Rousseau; Laurence Brugières; Olivier Caron; Jean-Christophe Sabourin; Isabelle Tournier; Stéphanie Baert-Desurmont; Thierry Frébourg; Gaëlle Bougeard

doi:10.1136/jmedgenet-2017-104976

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Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

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Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

Mariette Renaux-Petel, Françoise Charbonnier, Jean-Christophe Théry, Pierre Fermey, Gwendoline Lienard, Jacqueline Bou, Sophie Coutant, Myriam Vezain, Edwige Kasper, Steeve Fourneaux, …

Journal of medical genetics, Vol.55(3), pp.173-180

01/03/2018

DOI: https://doi.org/10.1136/jmedgenet-2017-104976

PMID: 29070607

Résumé

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

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Titre: Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome
Créateurs - sans rôle: Mariette Renaux-Petel - Department of Paediatric Surgery, Rouen University Hospital, Rouen, France
Françoise Charbonnier - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Jean-Christophe Théry - Department of Medical Oncology, Henri Becquerel Centre, Rouen, France
Pierre Fermey - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Gwendoline Lienard - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Jacqueline Bou - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Sophie Coutant - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Myriam Vezain - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Edwige Kasper - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Steeve Fourneaux - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Sandrine Manase - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Maud Blanluet - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Bruno Leheup - Centre Hospitalier Régional et Universitaire de Nancy
Ludovic Mansuy - Centre Hospitalier Régional et Universitaire de Nancy
Jacqueline Champigneulle - Department of Pathology, Nancy University Hospital, Nancy, France
Céline Chappé - Department of Paediatric Oncology, Rennes University Hospital, Rennes, France
Michel Longy - Department of Molecular Genetics, Bergonié Institute, Bordeaux, France
Nicolas Sévenet - Department of Molecular Genetics, Bergonié Institute, Bordeaux, France
Brigitte Bressac-de Paillerets - Department of Medical Biology and Pathology, and Inserm U, Gustave Roussy, University of Paris-Saclay, Villejuif, France
Léa Guerrini-Rousseau - Child and Adolescent Cancer Department, Gustave Roussy Cancer Campus, Villejuif, France
Laurence Brugières - Child and Adolescent Cancer Department, Gustave Roussy Cancer Campus, Villejuif, France
Olivier Caron - Department of Oncology, Gustave Roussy Cancer Campus, Villejuif, France
Jean-Christophe Sabourin - Department of Pathology, Rouen University Hospital, Rouen, France
Isabelle Tournier - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Stéphanie Baert-Desurmont - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Thierry Frébourg - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Gaëlle Bougeard - Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U and Rouen University Hospital, Rouen, France
Détails de publication: Journal of medical genetics, Vol.55(3), pp.173-180
Identifiants: 99162955909311
Unité académique: Institut des Biomolécules Max Mousseron - IBMM
Langue: English
Type de ressource: Journal article