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

Guido Di Dalmazi; Barbara Altieri; Claus Scholz; Silviu Sbiera; Michaela Luconi; Jens Waldmann; Darko Kastelan; Filippo Ceccato; Iacopo Chiodini; Giorgio Arnaldi; Anna Riester; Andrea Osswald; Felix Beuschlein; Sascha Sauer; Martin Fassnacht; Silke Appenzeller; Cristina Ronchi

doi:10.1210/clinem/dgaa616

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

Guido Di Dalmazi, Barbara Altieri, Claus Scholz, Silviu Sbiera, Michaela Luconi, Jens Waldmann, Darko Kastelan, Filippo Ceccato, Iacopo Chiodini, Giorgio Arnaldi, Anna Riester, Andrea Osswald, Felix Beuschlein, Sascha Sauer, Martin Fassnacht, Silke Appenzeller, Cristina Ronchi

Metabolism and Systems Science

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3 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	e4459–e4473
Number of pages	15
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	105
Issue number	12
Early online date	1 Sept 2020
DOIs	https://doi.org/10.1210/clinem/dgaa616
Publication status	Published - Dec 2020

Keywords

adrenocortical adenoma
Cushing syndrome
mild autonomous cortisol excess
transcriptome
gene fusions
long non-coding RNA
Mild autonomous cortisol excess
Transcriptome
Adrenocortical adenoma
Gene fusions
Long non-coding RNA

ASJC Scopus subject areas

Biochemistry, medical
Endocrinology
Biochemistry
Clinical Biochemistry
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1210/clinem/dgaa616Licence: None: All rights reserved

DalmaziG2020RNASequencing
Guido Di Dalmazi, Barbara Altieri, Claus Scholz, Silviu Sbiera, Michaela Luconi, Jens Waldman, Darko Kastelan, Filippo Ceccato, Iacopo Chiodini, Giorgio Arnaldi, Anna Riester, Andrea Osswald, Felix Beuschlein, Sascha Sauer, Martin Fassnacht, Silke Appenzeller, Cristina L Ronchi, RNA-Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights, The Journal of Clinical Endocrinology & Metabolism, , dgaa616, https://doi.org/10.1210/clinem/dgaa616
Accepted author manuscript, 348 KBLicence: None: All rights reserved

https://doi.org/10.1210/clinem/dgaa616Licence: None: All rights reserved

Cite this

Dalmazi, G. D., Altieri, B., Scholz, C., Sbiera, S., Luconi, M., Waldmann, J., Kastelan, D., Ceccato, F., Chiodini, I., Arnaldi, G., Riester, A., Osswald, A., Beuschlein, F., Sauer, S., Fassnacht, M., Appenzeller, S., & Ronchi, C. (2020). RNA-sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights. Journal of Clinical Endocrinology and Metabolism, 105(12), e4459–e4473. https://doi.org/10.1210/clinem/dgaa616

@article{e24ea80166234cd0b42959a8a913e00c,

title = "RNA-sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights",

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.",

keywords = "adrenocortical adenoma, Cushing syndrome, mild autonomous cortisol excess, transcriptome, gene fusions, long non-coding RNA, Mild autonomous cortisol excess, Transcriptome, Adrenocortical adenoma, Gene fusions, Long non-coding RNA",

author = "Dalmazi, {Guido Di} and Barbara Altieri and Claus Scholz and Silviu Sbiera and Michaela Luconi and Jens Waldmann and Darko Kastelan and Filippo Ceccato and Iacopo Chiodini and Giorgio Arnaldi and Anna Riester and Andrea Osswald and Felix Beuschlein and Sascha Sauer and Martin Fassnacht and Silke Appenzeller and Cristina Ronchi",

year = "2020",

month = dec,

doi = "10.1210/clinem/dgaa616",

language = "English",

volume = "105",

pages = "e4459–e4473",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "12",

}

Dalmazi, GD, Altieri, B, Scholz, C, Sbiera, S, Luconi, M, Waldmann, J, Kastelan, D, Ceccato, F, Chiodini, I, Arnaldi, G, Riester, A, Osswald, A, Beuschlein, F, Sauer, S, Fassnacht, M, Appenzeller, S & Ronchi, C 2020, 'RNA-sequencing and somatic mutation status of adrenocortical tumors: novel pathogenetic insights', Journal of Clinical Endocrinology and Metabolism, vol. 105, no. 12, pp. e4459–e4473. https://doi.org/10.1210/clinem/dgaa616

TY - JOUR

T1 - RNA-sequencing and somatic mutation status of adrenocortical tumors

T2 - novel pathogenetic insights

AU - Dalmazi, Guido Di

AU - Altieri, Barbara

AU - Scholz, Claus

AU - Sbiera, Silviu

AU - Luconi, Michaela

AU - Waldmann, 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

PY - 2020/12

Y1 - 2020/12

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 - mild autonomous cortisol excess

KW - transcriptome

KW - gene fusions

KW - long non-coding RNA

KW - Mild autonomous cortisol excess

KW - Transcriptome

KW - Adrenocortical adenoma

KW - Gene fusions

KW - Long non-coding RNA

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U2 - 10.1210/clinem/dgaa616

DO - 10.1210/clinem/dgaa616

M3 - Article

SN - 0021-972X

VL - 105

SP - e4459–e4473

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 12

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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