We found a statistically significant correlation between the expression of p53, p21, Ki67 and the differential diagnosis of adrenal cortical adenoma and adrenocortical carcinoma (for proteins: p53 p=0.010, for p21 p=0.010, for Ki67 p<0.001).
Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.
The finding that only a minority of adrenocortical tumors with 17p13 LOH had either a VNTR1 LOH or a TP53 mutation indicates that TP53 might not be the only or major tumor suppressor gene at 17p13 involved in adrenocortical cancer progression.
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.
Adrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the TP53 gene.
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.