GERM-LINE P53 MUTATIONS IN 15 FAMILIES WITH LI-FRAUMENI SYNDROME

Germ-line mutations of the tumor-suppressor gene p53 have been observe d in some families with the Li-Fraumeni syndrome (LFS), a familial can cer syndrome in which affected relatives develop a diverse set of earl y-onset malignancies including breast carcinoma, sarcomas, and brain t umors. The analysis of the p53 gene in LFS families has been limited, in most studies to date, to the region between exon 5 and exon 9. In o rder to determine the frequency and distribution of germ-line p53 muta tions in LFS, we sequenced the 10 coding exons of the p53 gene in lymp hocytes and fibroblast cell lines derived from 15 families with the sy ndrome. Germ-line mutations were observed in eight families. Six mutat ions were missense mutations located between exons 5 and 8. One mutati on was a nonsense mutation in exon 6, and one mutation was a splicing mutation in intron 4, generating aberrant shorter p53 RNA(s). In three families, a mutation of the p53 gene was observed in the fibroblast c ell line derived from the proband. However, the mutation was not found in affected relatives in two families and in the blood from the one i ndividual, indicating that the mutation probably occurred during cell culture in vitro. In four families, no mutation was observed. This stu dy indicates that germ-line p53 mutations in LFS are mostly located be tween exons 5 and 8 and that similar to 50% of patients with LFS have no germ-line mutations in the coding region of the p53 gene. The obser vation of p53 mutations occurring during primary cultures of human fib roblasts shows that analysis for germ-line p53 mutations must be perfo rmed on cells that have not been grown in vitro.