Li-Fraumeni syndrome: update, new data and guidelines for clinical management

The Li-Fraumeni syndrome (LFS) is an inherited from of cancers, affecting c hildren and young adults, and characterized by a wide spectrum of tumors, i ncluding soft-tissue and bone sarcomas, brain tumours, adenocortical tumour s and premenopausal breast cancers. In most of the families, LFS results fr om germline mutations of the tumor suppressor TP53 gene encoding a transcri ptional factor able to regulate cell cycle and apoptosis when DNA damage oc curs. Recently, germline mutations of hCHK2, encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The L FS working group recommendations are the following: (i) positive testing (s creening for a germline TP53 mutation in a patient with a tumor) can be off ered both to children and adults in the concert of genetic counseling assoc iated to psychological support, to confirm the diagnosis of LFS an a molecu lar basis. This will allow to offer to the patient a regular clinical revie w in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 i ndications for positive testing are : a proband with a tumor belonging to t he narrow LFS spectrum and developed before age 36 and at least, a first- o r second-degree relative with a LFS spectrum tumor, before age 46 or a pati ent with multiple primary tumors, 2 of which belonging to the narrow LFS sp ectrum, the first being developed before 36 or a child with an adrenocortic al tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors, the prognosis of some tumors, the impossibility to ensure an efficient early detection, and the risk for mut ation carriers to develop multiple primary tumors justify, that prenatal di agnosis might be considered in affected families.