TP53, hChk2, and the Li-Fraumeni Syndrome

In 1969 Li and Fraumeni (1 ,2 ) reported a systematic epidemiologic study of the incidence of cancers in relatives of children with rhabdomyosarcoma (RMS). They noted five families of 648 probands in which a sib or cousin was also affected by sarcoma, and furthermore prospective studies of four of these families revealed a strikingly increased frequency of several types of cancer. Twenty-four families were subsequently studied in detail by the same groups (3 ), and a definition of what has now been termed Li-Fraumeni syndrome (LFS) was derived. Classic LFS is defined by a proband with a sarcoma aged under 45 years with a first degree relative with any cancer under 45 and an additional first- or second-degree relative in the same lineage with any cancer under 45, or a sarcoma at any age. This definition is still widely used, but other groups have introduced more relaxed definitions taking into account a more extensive knowledge of the range of tumors identified in families, and the ages of onset. One of the most widely used was defined by Birch et al. (4 ) as Li-Fraumeni-like (LFL) and is a proband with any childhood tumor, or sarcoma, brain tumor, or adrenocortical tumor under 45 years, plus a first- or second-degree relative with a typical LFS tumor at any age and another first- or second-degree relative with any cancer under the age of 60. In all the discussions that follow, the above definitions of LFS and LFL will be used. Typical LFS tumors in this context include sarcomas, brain and breast tumors, and childhood adrenocortical carcinoma.