In:
Journal of the Endocrine Society, The Endocrine Society, Vol. 4, No. Supplement_1 ( 2020-05-08)
Kurzfassung:
Background: The pathogenesis of adrenocortical tumors (ACTs) in the pediatric population is partially known, and few prognostic factors have been identified in this age group. Recently, ATRX and DAXX have been implicated in the pathogenesis and prognosis of a variety of cancers. Their altered function has been shown to affect telomere length through a telomerase-independent mechanism. Objective: To investigate ATRX and DAXX gene expression, ATRX and DAXX protein expression, and telomere length, as well as their clinical significance, in ACT samples from pediatric patients. Methods: The records of 110 pediatric patients with available ACT samples were reviewed. ATRX, DAXX, TERT and TERC gene expression was assessed by qPCR (n = 100 ACTs; n = 12 normal adrenals). ATRX and DAXX protein expression was assessed by IHC (n = 45 ACTs). Telomere length was assessed by qPCR (n = 64 ACTs). For survival analysis, Kaplan-Meier curves were obtained. For association analysis, simple linear regression models were adjusted. Results: Most patients were female (70.9%) and harbored germline TP53 mutations (90.2%). Median age at diagnosis was 21.1 months (2.1 – 199). Younger patients ( & lt; 3 years) had better survival (p & lt; 0.01), while those with metastasis at diagnosis and carcinomas (classified by the Wieneke score) had worse survival (p & lt; 0.01). ATRX gene expression was decreased (p & lt; 0.01), while DAXX gene expression was increased (p & lt; 0.01) in ACTs, compared to normal adrenals. ATRX gene expression was even lower in the context of the germline TP53 (R337H) mutation (p & lt; 0.01). TERT expression was not detected in ACTs or normal adrenals, and TERC expression was not altered (p = 0.69). ATRX protein expression was lost in the majority of ACTs (95.6%), while DAXX was lost in a minority (21.1%). There was no association between gene or protein expression and disease-free or overall survival. There was a significant association between decreased ATRX and DAXX gene expression and increased telomere length (p & lt; 0.01 and p = 0.03, respectively). Conclusion: In pediatric ACTs, decreased ATRX and DAXX gene expression was associated with increased telomere length, independently of TERT or TERC expression. In these tumors, ATRX gene expression was decreased and ATRX protein expression was overall lost, while DAXX gene expression was increased and DAXX protein expression was overall retained. No significant association between these alterations and prognosis was found in this cohort. These findings suggest that ATRX and DAXX altered function may be more involved in the pathogenesis of pediatric ACTs than in the prognosis of the affected patients.
Materialart:
Online-Ressource
ISSN:
2472-1972
DOI:
10.1210/jendso/bvaa046.1369
Sprache:
Englisch
Verlag:
The Endocrine Society
Publikationsdatum:
2020
ZDB Id:
2881023-5
