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


  • G. Di Dalmazi
  • B. Altieri
  • C. Scholz
  • S. Sbiera
  • M. Luconi
  • J. Waldman
  • D. Kastelan
  • F. Ceccato
  • I. Chiodini
  • G. Arnaldi
  • A. Riester
  • A. Osswald
  • F. Beuschlein
  • S. Sauer
  • M. Fassnacht
  • S. Appenzeller
  • C.L. Ronchi


  • Journal of Clinical Endocrinology & Metabolism


  • J Clin Endocrinol Metab 105 (12): dgaa616


  • 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.