Novel germline mutation of the p53 tumor suppressor gene in a child with incidentally discovered adrenal cortical carcinoma.

Purpose: We report a case of adrenal cortical carcinoma in an infant, which was incidentally discovered by renal sonography after a urinary tract infection. The previous death of a sibling after rhabdomyosarcoma in infancy prompted a search for a heritable p53 tumor suppressor gene mutation in this family.

Patients and methods: Starting with frozen adrenal carcinoma tissue, polymerase chain reaction (PCR) amplification followed by direct sequencing of exons 4-8 of p53 was used to search for a mutation. When a mutation was identified in exon 6 of the tumor p53 sequence, PCR amplification and direct sequencing of exon 6 alone was then performed on DNA from peripheral blood lymphocytes (PBLs) of all immediate family members to determine whether a germline mutation was present. A different set of primers was used by a second laboratory at our institution to independently confirm the presence of the mutation in the adrenal carcinoma and in paraffin-embedded rhabdomyosarcoma tissue of the deceased sibling.

Results: A C-to-T transition was identified at a CpG site in codon 196 resulting in a change from arginine to a stop codon (CGA to TGA). The identical mutation, present as the sole p53 allele in the tumor DNA samples and in the heterozygous state with wild type p53 allele in DNA from PBLs (germline), was found in the adrenal carcinoma, the rhabdomyosarcoma, and the PBLs of the tumor-bearing child and her healthy father and 5-year-old brother. This nonsense mutation of p53 has never before been reported in the germline. The extended pedigree showed only one known additional cancer.

Conclusions: A novel germline p53 mutation was identified by investigation of a sibling pair with cancers associated with the Li-Fraumeni syndrome in a family with an otherwise negative history for cancer. The implications of this case for identification of carriers of p53 germline mutations and their clinical management are discussed.