Clinical Features and Outcomes in Children with Adrenocortical Tumors without Germline TP53 Mutations Described

Researchers have described clinical features and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations, according to a study recently published in the Journal of Clinical Oncology.

Emilia Modolo Pinto, PhD, Raul C. Ribeiro, MD, and colleagues of St. Jude Children’s Research Hospital in Memphis, Tenn., point out that ACTs are cancers caused mostly by germline mutations in the tumor suppressor gene TP53, but are also rarely associated with genetic constitutional disorders like Beckwith-Wiedemann syndrome (BWS), and that approximately half of children with ACTs don’t actually have TP53 germline mutations, and the tumorigenesis and tumor progression in these children are not well understood.

So the team looked at genomic DNA in 60 children without germline TP53 mutations (42 girls and 18 boys) with a median age of 3.3 years (0.25 years to 21.7 years), analyzing for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. They also evaluated beta-catenin express and Ki-67 labeling index (LI). “Primary endpoints were progression-free (PFS) and overall survival”.

The researchers analyzed TP53 in 54 of the 60 patients and observed somatic TP53 alterations in nine samples. One sample showed complete deletion of TP53. B-catenin alterations were seen in 43% of cases. “Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively,” the authors write. “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 [greater than or equal to] 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI [less than] 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).” Of note, six of nine patients in the study showed germline abnormalities of chromosome 11p15 but did not have clinical signs of BWS.

The authors write that these results show significant overlap in children with germline TP53 mutations (mutTP53-ACTs) and those without (wtTP53-ACTs). They also show differences between the two groups. “Approximately 90% of patients with mutTP53-ACTs develop adrenocortical tumors by 5 years of age (peak incidence, 1 to 3 years); thereafter, the risk decreases and remains low throughout life,” the authors write. “In contrast, 37% of our patients with wtTP53-ACTs were diagnosed after the age of 5 years. More than 90% of children with mutTP53-ACTs secrete androgens or androgens plus cortisol, whereas this pattern of hormonal secretion is seen in only approximately 55% of patients with wtTP53-ACTs.”

The researchers conclude that clinical features and prognostic factors in children with ACTs, with and without TP53 mutations, overlap, but genetic alterations contributing to the tumors are diverse between both groups. “Based on this study and other previous findings, detailed analysis of constitutional 11p15 abnormalities, including genetic and epigenetic alterations, should be considered in all children with ACTs irrespective of the absence of features of BWS or other growth disorders,” the authors write. “We also recommend that Ki-67 LI be included in histologic characterization to improve the pathologic classification of pediatric ACT.”