Li-Fraumeni syndrome – a molecular and clinical review

Abstract

In 1969 Li and Fraumeni identified, from a systematic study of 648 children with rhabdomyosarcomas, five families in which a sibling or a cousin was affected by sarcoma (Li and Fraumeni, 1969a, b). A prospective study of four of the original families indicated that there was a significantly increased risk of cancer within these families, particularly premenopausal breast cancer, as well as a significant excess of second malignancies (Li and Fraumeni, 1982). The term 'Li-Fraumeni syndrome' was used initially by Pearson et al (1982) and is now the most common term for this dominant inherited cancer syndrome. Studies from our own group on a population-based series of children with soft-tissue sarcoma (Birch et al, 1984; 1990) and a USA hospital-based series of survivors of childhood soft-tissue sarcomas from Strong's group in the USA (Strong et al, 1987) confirmed that the familial clustering was due to inherited predisposition and not to environmental factors. Twenty-four families, defined using strict criteria, were subsequently studied by the Li and Fraumeni groups (Li et al, 1988). Such families are now regarded as having 'classic' Li-Fraumeni syndrome (LFS), namely a proband aged under 45 years with a sarcoma having a first-degree relative aged under 45 years with any cancer and an additional firstor second-degree relative aged under 45 years in the same lineage with any cancer or a sarcoma at any age (Li et al, 1988). This study by Li et al (1988) indicated that the spectrum of tumours within the syndrome included acute leukaemia, premenopausal breast carcinoma, brain and adrenocortical tumours as well as bone and soft-tissue sarcomas. Other studies have indicated that a number of other cancers may occur at an increased frequency in these families, notably melanoma, germ cell tumours, Wilms' tumours, gastric and pancreatic carcinomas and lung cancer (Hartley et al, 1987; 1989; Strong et al, 1987; Varley et al, 1995; 1997a). While the definition of classic LFS has become generally accepted, a number of groups have relaxed the description to include incomplete Li-Fraumeni syndrome (a proband with an affected first-degree relative; Brugieres et al, 1993) and LiFraumeni-like syndrome (LFL). Two groups have defined LFL families independently but using different criteria. Eeles (1995) defined LFL as a clustering of two different tumours (both characteristic of LFS) in individuals who are firstor second-degree relatives of any age. Our own group has defined LFL by more stringent criteria: a proband with any childhood tumour or sarcoma, brain tumour or adrenocortical tumour under 45 years plus a firstor second-degree relative with a typical LFS tumour at