TY - JOUR T1 - Contribution of de novo and mosaic <em>TP53</em> mutations to Li-Fraumeni syndrome JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2017-104976 SP - jmedgenet-2017-104976 AU - Mariette Renaux-Petel AU - Françoise Charbonnier AU - Jean-Christophe Théry AU - Pierre Fermey AU - Gwendoline Lienard AU - Jacqueline Bou AU - Sophie Coutant AU - Myriam Vezain AU - Edwige Kasper AU - Steeve Fourneaux AU - Sandrine Manase AU - Maud Blanluet AU - Bruno Leheup AU - Ludovic Mansuy AU - Jacqueline Champigneulle AU - Céline Chappé AU - Michel Longy AU - Nicolas Sévenet AU - Brigitte Bressac-de Paillerets AU - Léa Guerrini-Rousseau AU - Laurence Brugières AU - Olivier Caron AU - Jean-Christophe Sabourin AU - Isabelle Tournier AU - Stéphanie Baert-Desurmont AU - Thierry Frébourg AU - Gaëlle Bougeard Y1 - 2017/10/23 UR - http://jmg.bmj.com/content/early/2017/10/25/jmedgenet-2017-104976.abstract N2 - 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. ER -