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.

Figure 1

The primary structure of p53 identifies multiple functional domains including a transactivation domain (TAD), proline-rich region (PRR), DNA-binding domain (DBD), tetramerization domain (TET) and regulatory region (REG). Codon positions are indicate by the numbers below the figure. The common “hotspot mutations” at codons 175, 245, 248, 249, 273 and 282 all lie within the DBD.

Figure 2

A. Data from the Surveillance Epidemiology and End Results registry recapitulate the bimodal distribution that has been previously described, with peaks in early childhood and middle-age (SEER Data, 1973-2008). B. Age of diagnosis of ACC among p53-germline mutation carriers. A unimodal distribution is observed with 54% of patients, presenting before age 2 and 92% prior to age 18. These data include 76 individuals with the R337H allele. A similar distribution is observed when excluding these individuals from the analysis (not shown). Data from IARC Database, R.15(Petitjean et al., 2007).

Figure 3

Codon distribution of p53 missense germline mutations in all individuals reported in IARC database (above) vs. in patients with ACC (below). The R337H mutation (arrows) is the most frequently reported mutation in both groups.