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

Autor: Michel Longy, Gaëlle Bougeard, Steeve Fourneaux, Léa Guerrini-Rousseau, Bruno Leheup, Edwige Kasper, Myriam Vezain, Jean-Christophe Sabourin, Ludovic Mansuy, Nicolas Sevenet, Isabelle Tournier, Sandrine Manase, Thierry Frebourg, Stéphanie Baert-Desurmont, Jacqueline Champigneulle, Pierre Fermey, Mariette Renaux-Petel, Jean-Christophe Thery, Françoise Charbonnier, Laurence Brugières, Maud Blanluet, Brigitte Bressac-de Paillerets, Jacqueline Bou, Sophie Coutant, Céline Chappé, Olivier Caron, Gwendoline Lienard
Přispěvatelé: Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Service d’Anatomie Pathologique [CHRU Nancy], Hématogoie pédiatrique, hôpital Sud, Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Journal of Medical Genetics
Journal of Medical Genetics, BMJ Publishing Group, 2018, pp.jmedgenet-2017-104976. ⟨10.1136/jmedgenet-2017-104976⟩
ISSN: 0022-2593
1468-6244
DOI: 10.1136/jmedgenet-2017-104976⟩
Popis: 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.
Databáze: OpenAIRE
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