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Original Article
Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome
  1. Mariette Renaux-Petel1,2,
  2. Françoise Charbonnier1,
  3. Jean-Christophe Théry1,3,
  4. Pierre Fermey1,
  5. Gwendoline Lienard1,
  6. Jacqueline Bou1,
  7. Sophie Coutant1,
  8. Myriam Vezain1,
  9. Edwige Kasper1,
  10. Steeve Fourneaux1,
  11. Sandrine Manase1,
  12. Maud Blanluet1,
  13. Bruno Leheup4,
  14. Ludovic Mansuy5,
  15. Jacqueline Champigneulle6,
  16. Céline Chappé7,
  17. Michel Longy8,
  18. Nicolas Sévenet8,
  19. Brigitte Bressac-de Paillerets9,
  20. Léa Guerrini-Rousseau10,
  21. Laurence Brugières10,
  22. Olivier Caron11,
  23. Jean-Christophe Sabourin1,12,
  24. Isabelle Tournier1,
  25. Stéphanie Baert-Desurmont1,
  26. Thierry Frébourg1,
  27. Gaëlle Bougeard1
  1. 1 Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France
  2. 2 Department of Paediatric Surgery, Rouen University Hospital, Rouen, France
  3. 3 Department of Medical Oncology, Henri Becquerel Centre, Rouen, France
  4. 4 Department of Clinical Genetics, Nancy University Hospital, Nancy, France
  5. 5 Department of Paediatric Oncology, Nancy University Hospital, Nancy, France
  6. 6 Department of Pathology, Nancy University Hospital, Nancy, France
  7. 7 Department of Paediatric Oncology, Rennes University Hospital, Rennes, France
  8. 8 Department of Molecular Genetics, Bergonié Institute, Bordeaux, France
  9. 9 Department of Medical Biology and Pathology, and Inserm U1186, Gustave Roussy, University of Paris-Saclay, Villejuif, France
  10. 10 Child and Adolescent Cancer Department, Gustave Roussy Cancer Campus, Villejuif, France
  11. 11 Department of Oncology, Gustave Roussy Cancer Campus, Villejuif, France
  12. 12 Department of Pathology, Rouen University Hospital, Rouen, France
  1. Correspondence to Professor Thierry Frébourg, Department of Genetics, Rouen University Hospital, Inserm U1245, IRIB, Normandy Centre for Genomic and Personalized Medicine, Faculty of Medicine, 22 boulevard Gambetta, 76183 Rouen CEDEX 1, France; thierry.frebourg{at}


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.

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  • MR-P and FC contributed equally.

  • Contributors GB and TF: conceived the project. BBP, LB, OC, CC, JC, LG, BL, ML, LM, J-CS and NS: contributed to patient recruitment and/or provided materials. MB, JB, FC, PF, SF, EK, GL, SM, MR-P and J-CT: contributed to molecular analyses. MV and SC: performed bioinformatics analyses. SB-D, JB, GB, FC, PF, TF, GL, M-RP, NS, J-CT and IT: performed data analysis and interpretation. MB, JB, GB, FC, SC, TF, M-RP and IT: wrote the manuscript. All authors: approved the manuscript.

  • Funding This work was supported by the INCa, the French National Cancer Institute and the ARC Foundation for Cancer Research.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.