TP53-Associated Pediatric Malignancies

Abstract

Although the majority of pediatric malignancies express wild-type p53, it is well established that germline TP53 mutations or functional inactivation of this pathway by other means contribute to childhood cancer. Epidemiology studies have revealed the existence of diverse inherited mutant TP53 alleles that display different levels of tumor suppressor activity, which correlate with cancer risk in terms of penetrance, age of onset, and tumor types. In this monograph, the authors describe those childhood cancers associated with functional inactivation of TP53 focusing on adrenocortical carcinoma as a model for tissues that are highly sensitive to loss of p53 activity.

Keywords: Arg337His; adrenocortical tumors; p53 mutation.

Figure 1.

TP53 mutations in childhood adrenocortical tumors. Blood and tumor samples were banked through the St. Jude Children’s Research Hospital International Pediatric Adrenocortical Tumor Registry (institutional review board approved). In a cohort of 48 patients with adrenocortical tumors, 36 TP53 mutations were detected (75%) within and outside the DNA binding domain. Three mutations were detected in multiple cases (Arg175His, Arg273Cys, and Arg337His). Most mutations represent single-nucleotide substitutions (red), although non-sense and complex mutations were also observed (black). The schematic outlines the coding region of TP53 spanning exons 1 to 11 (colors represent functional domains).