2 LI-FRAUMENI-SYNDROME FAMILIES WITH NOVEL GERMLINE P53 MUTATIONS - LOSS OF THE WILD-TYPE P53 ALLELE IN ONLY 50-PERCENT OF TUMORS

We describe two Li-Fraumeni syndrome families. Family A was remarkable for two early childhood cases of adrenocortical tumours, family B for a high incidence of many characteristic cancers, including a childhoo d case of choroid plexus tumour. Using direct sequencing, we analysed exons 5-9 of the p53 gene in constitutional DNA of individuals from bo th families and found two novel germline mutations in exon 5. In famil y A, we detected a point substitution in codon 138 (GCC to CCC), which resulted in the replacement of the alanine by a proline residue. Fami ly B harboured a single-base pair deletion in codon 178 (CAC to -AC), resulting in a frameshift and premature chain termination. Three out o f six tumours examined from both families, a renal cell carcinoma, a r habdomyosarcoma and a breast cancer, showed loss of heterozygosity and contained only the mutant p53 allele. The remaining three neoplasms, both adrenocortical tumours and the choroid plexus tumour retained het erozygosity. Immunohistochemistry with anti-p53 antibody confirmed acc umulation of p53 protein in tumours with loss of heterozygosity, while the remaining tumours were p53 negative. These results support the vi ew that complete loss of activity of the wild-type p53 need not be the initial event in the formation of all tumours in Li-Fraumeni individu als.