Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome

Editor—The Li-Fraumeni syndrome (LFS) represents one of the most devastating genetic predispositions to cancers. This rare syndrome, affecting children and young adults, is characterised by a wide spectrum of early onset malignancies including bone and soft tissue sarcomas, brain tumours, adrenocortical tumours, and premenopausal breast cancers.1 LFS was initially defined using stringent criteria2: (1) a proband with a sarcoma diagnosed before the age of 45, (2) a first degree relative with cancer before the age of 45, and (3) another first or second degree relative with either a sarcoma diagnosed at any age or any cancer diagnosed under the age of 45. Subsequently, Birch et al 3 defined Li-Fraumeni-like (LFL) syndrome as a proband with any childhood tumour or sarcoma, brain tumour, or adrenocortical tumour under 45 years, plus a first or second degree relative with a typical LFS tumour at any age and another first or second degree relative with any cancer under the age of 60. Eeles4 proposed more relaxed criteria for LFL: a clustering of two typical LFS tumours in subjects who are first or second degree relatives at any age. Since the original reports of germline mutations of the tumour suppressor gene TP53 in LFS,5 6 numerous studies have shown that germline TP53 mutations can be detected in approximately 70% of LFS families and 20% of LFL families,1 suggesting the possible involvement of other genes in LFS. This hypothesis was recently confirmed by the detection, in one LFS family and one family suggestive of LFS, of germline mutations of hCHK2 , the human homologue of the Saccharomyces cerevisiae RAD53 gene, located on chromosome 22q12.7 8 hCHK2 encodes a kinase, which is able to phosphorylate, in response to DNA damage, the Cdc25C phosphatase involved in the G2 checkpoint …