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

Autor:	Renaux-Petel M; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.; Department of Paediatric Surgery, Rouen University Hospital, Rouen, France., Charbonnier F; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Théry JC; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.; Department of Medical Oncology, Henri Becquerel Centre, Rouen, France., Fermey P; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Lienard G; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Bou J; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Coutant S; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Vezain M; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Kasper E; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Fourneaux S; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Manase S; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Blanluet M; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Leheup B; Department of Clinical Genetics, Nancy University Hospital, Nancy, France., Mansuy L; Department of Paediatric Oncology, Nancy University Hospital, Nancy, France., Champigneulle J; Department of Pathology, Nancy University Hospital, Nancy, France., Chappé C; Department of Paediatric Oncology, Rennes University Hospital, Rennes, France., Longy M; Department of Molecular Genetics, Bergonié Institute, Bordeaux, France., Sévenet N; Department of Molecular Genetics, Bergonié Institute, Bordeaux, France., Paillerets BB; Department of Medical Biology and Pathology, and Inserm U1186, Gustave Roussy, University of Paris-Saclay, Villejuif, France., Guerrini-Rousseau L; Child and Adolescent Cancer Department, Gustave Roussy Cancer Campus, Villejuif, France., Brugières L; Child and Adolescent Cancer Department, Gustave Roussy Cancer Campus, Villejuif, France., Caron O; Department of Oncology, Gustave Roussy Cancer Campus, Villejuif, France., Sabourin JC; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.; Department of Pathology, Rouen University Hospital, Rouen, France., Tournier I; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Baert-Desurmont S; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Frébourg T; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France., Bougeard G; Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2018 Mar; Vol. 55 (3), pp. 173-180. Date of Electronic Publication: 2017 Oct 25.
DOI:	10.1136/jmedgenet-2017-104976
Abstrakt:	Background: Development 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 Results: Among 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. Conclusions: This 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. Competing Interests: Competing interests: None declared. (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
Databáze:	MEDLINE
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