Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children’s Oncology Group Study

Abstract

Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.

Clinical, Genetic, and Prognostic Features of Adrenocortical Tumors in Children: A 10-Year Single-Center Experience

“…Interestingly, Pinto et al (48) have investigated the clinicopathologic characteristics and outcomes of children with ACT without germline TP53 mutations. They found overlapping features with those reported for children with germline TP53 mutations, highlighting the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACT (48).…”

Signal Transduction in Diffuse Intrinsic Pontine Glioma

“…TP53 mutations are present in 42–77% of DIPGs, making it the most common mutation after H3, and co‐occur with H3.3K27M mutations, wild‐type H3 DIPGs, and DIPGs harboring PDGFR amplification . TP53 mutations within the core DNA‐binding or tetramerisation domains are mutational hotspots in DIPG, which either alter conformation, or lead to premature truncation, respectively. Mutations in several phosphorylation sites of p53 lead to the loss of both DNA‐binding capacity and protein stability.…”

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

“…About 50% of pediatric ACTs are associated with germline TP53 variants that lead to more complex genomic landscapes [26]. Although discrete genomic changes were not independently associated with prognosis, complex genomic alterations tended to portend an unfavorable outcome [27]. Furthermore, TP53 variants observed in pediatric adrenocortical tumors did not correspond to the conventional hotspot variants associated with classic Li-Fraumeni syndrome (LFS), and most retain a wide range of functionality [28,29].…”