RNA-Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights

Research output: Contribution to journalArticlepeer-review


  • Guido Di Dalmazi
  • Barbara Altieri
  • Claus Scholz
  • Silviu Sbiera
  • Michaela Luconi
  • Jens Waldmann
  • Darko Kastelan
  • Filippo Ceccato
  • Iacopo Chiodini
  • Giorgio Arnaldi
  • Anna Riester
  • Andrea Osswald
  • Felix Beuschlein
  • Sascha Sauer
  • Martin Fassnacht
  • Silke Appenzeller

Colleges, School and Institutes


Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure.

To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms.

Cross-sectional study.

University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT).

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).


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.

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.

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.


Original languageEnglish
Article numberdgaa616
JournalJournal of Clinical Endocrinology and Metabolism
Publication statusPublished - 1 Sep 2020


  • adrenocortical adenoma, Cushing syndrome, mild autonomous cortisol excess, transcriptome, gene fusions, long non-coding RNA