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 rhabdomyosarcom a in infancy prompted a search for a heritable p53 tumor suppressor ge ne mutation in this family. Patients and Methods: Starting with frozen adrenal carcinoma tissue, polymerase chain reaction (PCR) amplificati on followed by direct sequencing of exons 4-8 of p53 was used to searc h for a mutation. When a mutation was identified in exon 6 of the tumo r p53 sequence, PCR amplification and direct sequencing of exon 6 alon e was then performed on DNA from peripheral blood lymphocytes (PBLs) o f all immediate family members to determine whether a germline mutatio n was present. A different set of primers was used by a second laborat ory at our institution to independently confirm the presence of the mu tation in the adrenal carcinoma and in paraffin-embedded rhabdomyosarc oma tissue of the deceased sibling. Results: A C-to-T transition was i dentified at a CpG site in codon 196 resulting in a change from argini ne to a stop codon (CGA to TGA). The identical mutation, present as th e sole p53 allele in the tumor DNA samples and in the heterozygous sta te with wild type p53 allele in DNA from PBLs (germline), was found in the adrenal carcinoma, the rhabdomyosarcoma, and the PBLs of the tumo r-bearing child and her healthy father and 5-year-old brother. This no nsense mutation of p53 has never before been reported in the germline. The extended pedigree showed only one known additional cancer. Conclu sions: A novel germline p53 mutation was identified by investigation o f a sibling pair with cancers associated with the Li-Fraumeni syndrome in a family with an otherwise negative history for cancer. The implic ations of this case for identification of carriers of p53 germline mut ations and their clinical management are discussed.