The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight

Language
en
Document Type
Article
Issue Date
2020-01-15
First published
2019-11-08
Issue Year
2019
Authors
Sbiera, Silviu
Kunz, Meik
Weigand, Isabel
Deutschbein, Timo
Dandekar, Thomas
Fassnacht, Martin
Editor
Publisher
MDPI
Abstract

Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways.

Journal Title
Cancers
Volume
11
Issue
11
Citation
Cancers 11.11 (2019): 1761. <https://www.mdpi.com/2072-6694/11/11/1761>
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