ESPE Abstracts (2023) 97 P1-200

1Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil. 2Boldrini Children´s Center, Campinas, Brazil. 3Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil

Background: Impairment of the chromatin remodeling factors ATRX and DAXX and telomeres abnormality play a role in cancer biology, influencing the clinical outcomes. However, their roles in adrenal tumorigenesis require broader investigation.

Aim: To evaluate ATRX and DAXX genotype and expression, telomere length, and the alternative lengthening of telomeres (ALT), as well as their clinical significance, in primary adrenocortical tumors ACT samples from pediatric patients.

Methods: 106 children with ACT (72% girls, median age 1.8 years), and their primary tumor samples were included. Tumor ATRX, DAXX, and TERT genotypes were assessed by whole exome sequencing (Illumina) and their relative gene expression by qPCR. ATRX and DAXX protein expression were evaluated by IHC. Telomere length was assessed by qPCR, and ALT by FISH. Patients’ progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier curves and log rank. A significance level of α=0.05 and 95% confidence intervals were used.

Results: Age at diagnosis below four years was associated with a better prognosis, while advanced disease and classification as carcinoma by the Wieneke score were associated with a worse prognosis. ATRX was mutated in 44.5%, and TERT in 37% of the tumors evaluated, which were all carriers of the p53 p.R337H germline mutation. ATRX mutations were not associated with ATRX gene expression, and none of the samples expressed TERT. Compared to control normal adrenals, ATRX gene expression was decreased (P<0.01), while DAXX gene expression was increased (P<0.01) in pediatric ACT. ATRX protein expression was lost in most samples (95.6%), being positive in two mutant samples. DAXX protein expression was lost in a minority (22.2%). There was a weak negative correlation between ATRX (ρ=-0.35; P=0.008) and DAXX (ρ=-0,3; P=0.023) gene expression and telomere length. ALT was present in 27.3% of ACT. ATRX and TERT mutations were not associated with telomere length nor with ALT. Patients whose tumors were concomitantly mutant for ATRX and TERT (n=4) had reduced PFS (P=0.006) and OS (P=0.003). There was no association between gene/protein expression, telomere length, or ALT and PFS or OS.

Conclusion: Abnormal ATRX and DAXX gene and protein expression are frequent in the pediatric ACT and influence the telomere length, but not the patients' clinical outcome. However, the co-occurrence of somatic mutations in ATRX and TERT is strongly associated with the unfavorable prognosis of these patients.

Volume 97

61st Annual ESPE (ESPE 2023)

The Hague, Netherlands
21 Sep 2023 - 23 Sep 2023

European Society for Paediatric Endocrinology 

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