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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; Ronchi, Cristina L (2020). RNA Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights. Journal of Clinical Endocrinology & Metabolism, 105(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 (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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Endocrinology, Diabetes and Metabolism
Life Sciences > Biochemistry
Life Sciences > Endocrinology
Life Sciences > Clinical Biochemistry
Health Sciences > Biochemistry (medical)
Language:English
Date:1 December 2020
Deposited On:16 Feb 2021 10:14
Last Modified:17 Feb 2021 21:00
Publisher:Oxford University Press
ISSN:0021-972X
OA Status:Closed
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1210/clinem/dgaa616
PubMed ID:32875319

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