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Endocrine Abstracts (2020) 70 YI3 | DOI: 10.1530/endoabs.70.YI3


1University of Bologna; 2University of Wurzburg; 3University of Bonn; 4University of Firenze; 5Mivendo Klinik Hamburg; 6University of Zagreb; 7University of Padova; 8University of Milan; 9Polytechinc University of Marche; 10Ludwig Maximilian University of Munich; 11University of Zurich; 12Berlin Institute of Medical Systems Biology; 13University of Birmingham

Background: Genetic alterations underlying the pathogenesis of autonomous cortisol secretion and early adrenocortical tumorigenesis have been identified in 40% of adrenocortical tumors (ACT). Nonetheless, the molecular events leading to development of ACT and steroid secretion remain obscure for a large proportion of patients.

Aim: Aims of our study were to investigate the relationship between transcriptome profile and genetic background in a large series of ACT and to identify novel potentially pathogenic molecular event by deep RNA-sequencing.

Methods: We collected snap-frozen tissue from patients with ACT and known genetic background among centers of the European Network for the Study of Adrenal Tumors (ENSAT). Details about somatic mutations were available from previous targeted Sanger sequencing or whole-exome sequencing (WES). We included in the study 52 adenomas (26 associated with Cushing syndrome [CS-CPA], 17 with mild autonomous cortisol secretion [MACS-CPA], and 9 endocrine-inactive, EIA) and 7 early-stage adrenocortical carcinomas (ACC). We performed deep RNA-sequencing for the analysis of gene expression, long non-coding RNA (lncRNA), and gene fusions. We investigated the correlation between RNA-sequencing results and genetic background (i.e. presence of mutations in driver genes - PRKACA, GNAS or CTNNB1, or no mutations in driver genes).

Results: Transcriptome analysis identified two major clusters for adenomas: cluster 1 with EIA and MACS-CPA with CTNNB1 mutations or no drivers and cluster 2 with CS-CPA and MACS-CPA with PRKACA or GNAS mutations and CS-CPA with no drivers. In cluster 2, FATE1 was among most common overexpressed genes. Overall, three CS-CPA with CTNNB1 mutations clustered close to ACC. The analysis of the lncRNA expression showed similar results, confirming the clusters identified in transcriptome profile. ACC showed a higher number of gene fusions per sample (average 8.14) than adenomas (0.79), whereas CTNNB1-CPA had an intermediate number of gene fusions per sample (1.7). We identified novel gene fusions, including an AKAP13-PDE8A fusion in a CS-CPA sample with no previously identified driver mutations.

Conclusions: MACS and EIA showed a similar transcriptome profile, independently of the genetic background. Still unrevealed molecular alterations might be involved in the pathogenesis of adrenocortical tumors associated with cortisol excess. CT

Volume 70

22nd European Congress of Endocrinology

05 Sep 2020 - 09 Sep 2020

European Society of Endocrinology 

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