SAT-222 Chromatin Remodeling Factors ATRX and DAXX and Telomeres Involvement in Pediatric Adrenocortical Tumors

Abstract Disclosure: M.F. Stecchini: None. A.B. Arruda: None. J. Marrero-Gutiérrez: None. M.R. Campos: None. I.A. Cardinalli: None. C.A. Scrideli: None. C.A. molina: None. S. Tucci: None. F.B. Coeli-Lacchini: None. A.C. Moreira: None. L.N. Ramalho: None. S.R. Brandalise: None. A.J. Yunes: None. R.Z. Vencio: None. F. Chahud: None. M. De Castro: None. S.R. Rauber Antonini: None. Background: ATRX protein, a chromatin remodeler and transcriptional regulator, plays a crucial role in essential cellular pathways by cooperating with DAXX and promoting histone modifications in the telomere area. Abnormal functioning ATRX and DAXX, as well as in telomeres, have been recognized as important elements for tumorigenesis and prognosis in different types of cancer. However, their roles in pediatric adrenocortical tumors (pACT) require broader investigation. Objective: To evaluate the presence and clinical significance of ATRX, DAXX, and TERT genotype, gene expression, protein expression, telomere length, and the alternative lengthening of telomeres (ALT) mechanism in primary pACT samples. Methods: Tumor ATRX, DAXX, and TERT genotypes were assessed by targeted exome sequencing and their relative gene expression by qPCR. IHC assessed ATRX and DAXX protein expression. Telomere length was assessed by qPCR and ALT by FISH. Normal adrenal cortices were used as controls. Patients' progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier curves. A significance level of α=0.05 was used. Results: Most of the analyzed 106 patients with pACT were female (71.7%) and harbored the TP53 p.R337H germline variant (84.9%). The median age at the diagnosis was 22.1 months. Age at diagnosis below four years was associated with a better prognosis, while advanced disease (IPACTR stages 3 and 4) and Wieneke score higher than three were associated with a worse prognosis. ATRX and TERT somatic variants were identified in 46% and 36% of the pACT, all from TP53 p.R337H germline variant carriers, and harbored the corresponding somatic TP53 variant. No DAXX variants were identified. ATRX variants were not associated with ATRX gene expression. None of the samples expressed TERT. Compared to control adrenals, ATRX gene expression was decreased (p<0.01), while DAXX gene expression was increased (p<0.01) in pACT. ATRX protein expression was lost in most samples (95.6%) but was positive in two wild-type 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 the ACT. ATRX or TERT variants were not associated with telomere length nor with ALT. Patients whose tumors had both ATRX and TERT variants (n=5) had reduced PFS (p=0.03) and OS (p=0.01). There was no association between gene/protein expression, telomere length, or ALT, and PFS or OS. Conclusions: Abnormal ATRX and DAXX gene and protein expression are frequent in pACT and appear to influence telomere length but not the patient's clinical outcome. However, the co-occurrence of somatic variants in ATRX and TERT is associated with an unfavorable prognosis for these patients. Presentation: Saturday, July 12, 2025