TY - JOUR
T1 - RNA sequencing and somatic mutation status of adrenocortical tumors
T2 - novel pathogenetic insights
AU - Di Dalmazi, Guido
AU - Altieri, Barbara
AU - Scholz, Claus
AU - Sbiera, Silviu
AU - Luconi, Michaela
AU - Waldman, Jens
AU - Kastelan, Darko
AU - Ceccato, Filippo
AU - Chiodini, Iacopo
AU - Arnaldi, Giorgio
AU - Riester, Anna
AU - Osswald, Andrea
AU - Beuschlein, Felix
AU - Sauer, Sascha
AU - Fassnacht, Martin
AU - Appenzeller, Silke
AU - Ronchi, Cristina L.
N1 - Publisher Copyright:
© Endocrine Society 2020.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Adrenocortical adenoma
KW - Cushing syndrome
KW - Gene fusions
KW - Long non-coding RNA
KW - Mild autonomous cortisol excess
KW - Transcriptome
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U2 - 10.1210/clinem/dgaa616
DO - 10.1210/clinem/dgaa616
M3 - Article
C2 - 32875319
AN - SCOPUS:85092681455
VL - 105
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 12
ER -