RNA-sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights

Item Type:	Article
Title:	RNA-sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights
Creators Name:	Di Dalmazi, G. and Altieri, B. and Scholz, C. and Sbiera, S. and Luconi, M. and Waldman, J. and Kastelan, D. and Ceccato, F. and Chiodini, I. and Arnaldi, G. and Riester, A. and Osswald, A. and Beuschlein, F. and Sauer, S. and Fassnacht, M. and Appenzeller, S. and Ronchi, C.L.
Abstract:	CONTEXT: Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. OBJECTIVE: To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms. DESIGN: Cross-sectional study. SETTING: University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT). PATIENTS: We collected snap-frozen tissue from patients with adrenocortical tumors (n=59) with known genetic background: 26 adenomas with Cushing syndrome (CS-CPAs), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs). INTERVENTION: RNA-sequencing. MAIN OUTCOME MEASURES: Gene expression, long non-coding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger-Sequencing, targeted panel- or whole-exome sequencing. RESULTS: Transcriptome analysis identified two major clusters for adenomas: Cluster 1 (n=32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n=18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, one with CTNNB1 and one with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation. CONCLUSIONS: MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.
Keywords:	Adrenocortical Adenoma, Cushing Syndrome, Mild Autonomous Cortisol Excess, Transcriptome, Gene Fusions, Long Non-Coding RNA
Source:	Journal of Clinical Endocrinology & Metabolism
ISSN:	0021-972X
Publisher:	Endocrine Society
Volume:	105
Number:	12
Page Range:	dgaa616
Date:	December 2020
Additional Information:	Copyright © Endocrine Society 2020. All rights reserved.
Official Publication:	https://doi.org/10.1210/clinem/dgaa616
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