PREVALENCE AND DIVERSITY OF CONSTITUTIONAL MUTATIONS IN THE P53 GENE AMONG 21 LI-FRAUMENI FAMILIES

The entire coding sequence of the p53 gene was analysed for the presen ce of mutations in 12 families conforming to a restricted definition o f Li-Fraumeni syndrome (classic LFS) and nine families with features o f LFS conforming to a broader definition. Mutations were detected in s even families. Six were point mutations with one each affecting codons 175, 180, and 220 and three affecting codon 248. The seventh was a de letion/ insertion mutation in exon 4. Germline mutations in p53 were a feature of families which included children with rhabdomyosarcoma and /or adrenal cortical carcinoma. Germline p53 mutations were detected i n six of the nine families with such tumors. An analysis of these 7 mu tations, together with 34 published examples, showed that more than on e-half were transitions at CpG dinucleotides, suggesting that the majo rity of germline p53 mutations may arise as a result of spontaneous ev ents. The most common cancers occurring in the 41 families with germli ne p53 mutations, in common with classic LPS, mere bone and soft tissu e sarcoma, breast cancer, brain tumors, leukemia, and adrenocortical c arcinoma, although less than one-half of the probands with germline p5 3 mutations came from classic LFS families. More than one-half of the cancers overall and nearly one-third of the breast cancers were diagno sed before 30 years of age. These observations have important implicat ions for asymptomatic carriers of germline p53 mutations, and there is a need for international collaboration in the development of protocol s for the management of such families.