Towards an understanding of the role of p53 in adrenocortical carcinogenesis

Abstract

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.

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

“…One hallmark of pediatric ACT in Brazil is the TP53 p.R337H germline mutation, which disrupts protein tetramer formation and reduces the p53 activity in higher pH levels (Wasserman et al 2012). Interestingly, in response to cellular stress such as oncogene activation, the p53 can shutdown the IGF pathway, reducing IGF2 and IGF1R expression and the receptor tyrosine phosphorylation (Sampaoli et al 2012).…”

R337H mutation of the TP53 gene as a clinical marker in cancer patients: a systematic review of literature

“…However, some tumors types found among the relatives could not be directly related to the R337H mutation because of external factors, such as lung cancer caused by smoking. Additionally, the estimated penetrance of the mutant allele was approximately 10% (Figueiredo et al, 2006;Wasserman et al, 2012). Although the mutation was found in nearly 100% of cases of ACT (Ribeiro et al, 2001), its frequency in the general population outside South and Southeast Brazil was low (Pianovski et al, 2006).…”

Adrenal Cortex Tumors and Hyperplasias

“…Its incidence is around 1 to 3 in 10.000.000 except in the southern regions of Brazil where it reaches 1 to 3 :1.000.000 (Agrons et al, 1999;Ribeiro et al, 2000, Wasserman et al, 2011.). In southern Brazil, these carcinomas are frequently associated with a particular mutation of TP53 (namely Arg337His) (Ribeiro et al, 1990).…”