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.
RNA sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights / 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.; Ronchi, C. L.. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 105:12(2020), pp. e4459-e4473. [10.1210/clinem/dgaa616]