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

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, Cristina Ronchi

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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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 Sept 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

ASJC Scopus subject areas

  • Biochemistry, medical
  • Endocrinology
  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism


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