PT  - JOURNAL ARTICLE
AU  - Renaux-Petel, Mariette
AU  - Charbonnier, Françoise
AU  - Théry, Jean-Christophe
AU  - Fermey, Pierre
AU  - Lienard, Gwendoline
AU  - Bou, Jacqueline
AU  - Coutant, Sophie
AU  - Vezain, Myriam
AU  - Kasper, Edwige
AU  - Fourneaux, Steeve
AU  - Manase, Sandrine
AU  - Blanluet, Maud
AU  - Leheup, Bruno
AU  - Mansuy, Ludovic
AU  - Champigneulle, Jacqueline
AU  - Chappé, Céline
AU  - Longy, Michel
AU  - Sévenet, Nicolas
AU  - Paillerets, Brigitte Bressac-de
AU  - Guerrini-Rousseau, Léa
AU  - Brugières, Laurence
AU  - Caron, Olivier
AU  - Sabourin, Jean-Christophe
AU  - Tournier, Isabelle
AU  - Baert-Desurmont, Stéphanie
AU  - Frébourg, Thierry
AU  - Bougeard, Gaëlle
TI  - Contribution of de novo and mosaic <em>TP53</em> mutations to Li-Fraumeni syndrome
AID  - 10.1136/jmedgenet-2017-104976
DP  - 2018 Mar 01
TA  - Journal of Medical Genetics
PG  - 173--180
VI  - 55
IP  - 3
4099  - http://jmg.bmj.com/content/55/3/173.short
4100  - http://jmg.bmj.com/content/55/3/173.full
SO  - J Med Genet2018 Mar 01; 55
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.