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

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Item Type:	Article
Title:	RNA-sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights
Creators Name:	Di Dalmazi, G., Altieri, B., Scholz, C., Sbiera, S., Luconi, M., Waldman, J., Kastelan, D., Ceccato, F., Chiodini, I., Arnaldi, G., Riester, A., Osswald, A., Beuschlein, F., Sauer, S., Fassnacht, M., 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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