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

Di Dalmazi, Guido; Altieri, Barbara; Scholz, Claus; Sbiera, Silviu; Luconi, Michaela; Waldman, Jens; Kastelan, Darko; Ceccato, Filippo; Chiodini, Iacopo; Arnaldi, Giorgio; Riester, Anna; Osswald, Andrea; Beuschlein, Felix; Sauer, Sascha; Fassnacht, Martin; Appenzeller, Silke und Ronchi, Cristina L. (2020): RNA Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights. In: Journal of Clinical Endocrinology & Metabolism, Bd. 105, Nr. 12, dgaa616

Abstract

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 (ElAs), 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 ElAs;Cluster 2 (n = 18) that comprised CRCPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNErl and 1 with GNAS mutation, clustered separately and relatively close to ACC. IncRNA 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 ElAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA orWnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0021-972X
• Sprache: Englisch