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


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- cortisol-producing adenoma [CPA]), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs).

Intervention: Ribonucleic acid (RNA) sequencing.

Main Outcome Measures: Gene expression, long noncoding 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 2 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, 1 with CTNNB1 and 1 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.


Original languageEnglish
Pages (from-to)e4459–e4473
Number of pages15
JournalJournal of Clinical Endocrinology and Metabolism
Issue number12
Early online date1 Sep 2020
Publication statusPublished - Dec 2020


  • adrenocortical adenoma, Cushing syndrome, mild autonomous cortisol excess, transcriptome, gene fusions, long non-coding RNA, Mild autonomous cortisol excess, Transcriptome, Adrenocortical adenoma, Gene fusions, Long non-coding RNA