The genetic predisposition to adrenocortical cancer in children has been well established in the Li-Fraumeni and Beckewith-Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF-2 locus at 11p15, respectively.
There were marked organ-specific differences in the mean age at which carriers of p53 germline mutations present with neoplastic disease: 5 years for adrenocortical carcinomas, 16 years for sarcomas, 25 years for brain tumors, 37 years for breast cancer, and almost 50 years for lung cancer.
Here, we review ∼15 years of research into an unusual germline TP53 mutation (p.R337H) that began with its detection in children with adrenocortical carcinoma (ACC), a remarkably rare childhood cancer that is associated with poor prognosis.
The low rate of cure of adrenocortical carcinomas (ACC) in children and adults is related to germ line TP53 mutation, late diagnosis, incomplete surgical resection, and lack of an efficient adjunctive therapy.
Allelic losses at the p53 and RB loci were detected in all tumor samples, suggesting that the p53 and RB genes are involved in the tumorigenesis of adrenocortical carcinoma.
More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma.
Our results suggest that the TP53 codon 72 polymorphism could be associated with susceptibility for adrenocortical cancer in the examined Polish patients.
Although codon 273 is a known hotspot region for p53 mutation, the patient's mutation, R273H, has not been associated with development of adrenal cortical carcinoma.
IGF-II mRNA levels were more than 10-fold higher in hormonally active adrenocortical carcinomas than in normal adult adrenals, and increased IGF-II-like immunoreactivity was detectable in these carcinomas.
Previous studies have identified overexpression of insulin-like growth factor 2 (IGF-2) and constitutive activation of β-catenin as key factors involved in the development of adrenocortical carcinoma.
The pathogenesis of the adrenocortical cancer (ACC) involves integration of molecular signals and the interplay of different downstream pathways (i.e.IGFII/IGF1R, β-catenin, Wnt, ESR1).
The xenografts precisely reproduced the dysregulation of the insulin-like growth factor (IGF) system [overexpression of the IGF-II and IGF-binding protein-2 (IGFBP-2) genes] typical of adrenocortical carcinoma.
We previously demonstrated that, in adrenocortical carcinoma (ACC), ERα is upregulated and that estradiol activates the IGF-II/IGF1R signaling pathways defining the role of this functional cross-talk in H295R ACC cell proliferation.
Treatment with KU758 is associated with overall statistically significant upregulation of long noncoding RNA expression, including the tumor suppressor GAS5, which is implicated in the β-catenin and mammalian target of rapamycin pathways in adrenocortical carcinoma.