An inherited <i>p53</i> mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma

TLDR

The study aimed to investigate the link between childhood adrenal cortical carcinoma and Li‑Fraumeni syndrome by examining cancer history and p53 status in Brazilian patients and families. The authors examined cancer histories and p53 status in 36 Brazilian patients and their families. They found that pediatric ACC is 10–15 times more common in southern Brazil, that 35 of 36 patients carried a germ‑line p53 R337H mutation with independent origins, that tumors lost the wild‑type allele and accumulated mutant p53, yet family members showed no increased cancer risk, indicating that R337H is a low‑penetrance, tissue‑specific contributor to pediatric ACC.

Abstract

The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10–15 times higher than that of pediatric ACC worldwide. Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating a founder effect. In tumor cells, the wild-type allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ACC.