Li-Fraumeni Syndrome

Abstract

Li-Fraumeni syndrome (LFS) is a rare inherited disease characterized by soft tissue sarcomas in children and young adults, early onset breast cancer in their close relatives, and frequent occurrence of adrenocortical and brain tumors, osteosarcomas, leukemia, and other neoplasms. Despite its rarity, the disease is of considerable clinical and biological interest for several reasons. First of all, LFS was one of the first cancer family syndromes in which an autosomal dominant type of genetic transmission was documented, initially on the basis of clinical reports on clustering of neoplasms in families, subsequently with segregation analysis, and finally with the observation of a continued excess of cancers in the follow-up. Second, germline mutations of the p53 tumor suppressor gene have been detected in several families with LFS; although the paradigm that “not all investigated families showed germline p53 mutations, and these were found not only in LFS” holds true, there is nevertheless no doubt that these observations represent a major advance towards the understanding of the molecular biology of inherited tumors. Third, if germline p53 mutations can be considered a biological marker of increased susceptibility to the tumor spectrum of LFS, then it is possible to identify asymptomatic individuals who are at risk of the disease, and to develop a long-term program of screening and follow-up. Finally, the “molecular definition” of increased susceptibility to cancer in LFS (i.e., p53 mutations) raises several clinical and ethical questions. For example, since tumor spectrum and age of onset of neoplasms in LFS are very wide, to devise an effective screening program for early detection of cancer in family members at risk might be extremely complex. Moreover, the benefit of reassuring a high-risk individual with a negative test (i.e., no p53 mutation) should be balanced by the unavoidable anxiety and possible social discrimination of asymptomatic subjects who may show p53 mutations.

Families with Li-Fraumeni syndrome are rare, but nevertheless recognition of such families is important in identifying individuals at risk, who may benefit from genetic counselling and screening. Of wider importance, such families provide a model of cancer susceptibility, not only to rare cancer, such as soft tissue sarcomas and adrenocortical tumours, but also to very common malignancies. (J. M. Birch 1990)