RT Journal Article SR Electronic T1 Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 173 OP 180 DO 10.1136/jmedgenet-2017-104976 VO 55 IS 3 A1 Mariette Renaux-Petel A1 Françoise Charbonnier A1 Jean-Christophe Théry A1 Pierre Fermey A1 Gwendoline Lienard A1 Jacqueline Bou A1 Sophie Coutant A1 Myriam Vezain A1 Edwige Kasper A1 Steeve Fourneaux A1 Sandrine Manase A1 Maud Blanluet A1 Bruno Leheup A1 Ludovic Mansuy A1 Jacqueline Champigneulle A1 Céline Chappé A1 Michel Longy A1 Nicolas Sévenet A1 Brigitte Bressac-de Paillerets A1 Léa Guerrini-Rousseau A1 Laurence Brugières A1 Olivier Caron A1 Jean-Christophe Sabourin A1 Isabelle Tournier A1 Stéphanie Baert-Desurmont A1 Thierry Frébourg A1 Gaëlle Bougeard YR 2018 UL http://jmg.bmj.com/content/55/3/173.abstract AB 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.