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.

Di Dalmazi G., Altieri B., Scholz C., Sbiera S., Luconi M., Waldman J., et al. (2020). RNA sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights. THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, 105(12), 4459-4473 [10.1210/clinem/dgaa616].

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

Arnaldi G.;
2020-01-01

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 (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.
2020
Di Dalmazi G., Altieri B., Scholz C., Sbiera S., Luconi M., Waldman J., et al. (2020). RNA sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights. THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, 105(12), 4459-4473 [10.1210/clinem/dgaa616].
File in questo prodotto:
File Dimensione Formato  
dgaa616.pdf

accesso aperto

Tipologia: Versione Editoriale
Dimensione 6.19 MB
Formato Adobe PDF
6.19 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/620730
Citazioni
  • ???jsp.display-item.citation.pmc??? 18
  • Scopus 22
  • ???jsp.display-item.citation.isi??? 21
social impact