Towards an understanding of the role of p53 in adrenocortical carcinogenesis

Adrenocortical carcinoma (ACC) is recognized to be a component tumor of the Li Fraumeni Syndrome (LFS), a familial cancer predisposition resulting from germline mutations in the p53 tumor-suppressor. p53 activity is tightly regulated by multiple post-translational mechanisms, disruption of which may lead to tumorigenesis. ACC is present in disproportionately high rates among p53-mutation carriers, suggesting tissue-specific manifestations of p53 deficiency. Additionally, p53-associated ACC demonstrates a strong predominance in infants and children. Several of the p53 alleles associated with pediatric ACC, however, retain significant wild-type activity and demonstrate incomplete penetrance, a finding distinct from other LFS-component tumors. In this review, we discuss the relationship between p53 and adrenocortical carcinogenesis, with specific focus on disease-specific alleles, tumorigenesis in the context of adrenal development and potential therapeutic approaches to p53-associated ACC.

► Adrenocortical carcinomas present in excess among carriers of germline p53 mutations. ► p53-associated ACC occurs predominantly in the pediatric age group. ► Pediatric ACC is associated with low-penetrance alleles & retained protein function. ► Tumorigenesis in children may relate to changes during neonatal adrenal development. ► Mouse models of p53-loss do not develop ACC.