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

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 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 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 mutations, allowed us to identify 6 additional cases of mosaic 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 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 mutation identification, medical laboratories in charge of testing should ensure the detection of mosaic mutations.