p53 compound heterozygosity in a severely affected child with Li-Fraumeni Syndrome

The Li-Fraumeni Syndrome (LFS) is a rare, dominantly inherited syndrome tha t features high risk of cancers in childhood and early adulthood. Affected families tend to develop bone and soft tissue sarcomas, breast cancers, bra in tumors, leukemias, and adrenocortical carcinomas. In some kindreds, the genetic abnormality associated with this cancer phenotype is a heterozygous germline mutation in the p53 tumor suppressor gene. Recently, we identifie d one patient who presented in early childhood with multiple primary cancer s and who harbored three germline p53 alterations (R156H and R267Q on the m aternal allele and R290H on the paternal allele), To classify the biologic effects of these alterations, functional properties of each of the p53 muta nts were examined using in vitro assays of cellular growth suppression and transcriptional activation. Each amino acid substitution conferred partial or complete loss of wild-type p53 function, but the child completed normal embryonic development. This observation has not been previously reported in a human, but is consistent with observations of normal embryogenesis in p5 3-deficient mice.