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Open AccessArticle

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

Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, D-97080 Würzburg, Germany
Comprehensive Cancer Center Mainfranken, University of Würzburg, D-97080 Würzburg, Germany
Chair of Medical Informatics, Friedrich-Alexander University of Erlangen-Nürnberg, D-91058 Erlangen, Germany
Department of Bioinformatics, Biocenter, University of Würzburg, D-97074 Würzburg, Germany
Author to whom correspondence should be addressed.
Cancers 2019, 11(11), 1761;
Received: 4 October 2019 / Revised: 28 October 2019 / Accepted: 4 November 2019 / Published: 8 November 2019
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. View Full-Text
Keywords: Cushing’s disease; pathogenesis; somatic mutations; deubiquitinases Cushing’s disease; pathogenesis; somatic mutations; deubiquitinases
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Sbiera, S.; Kunz, M.; Weigand, I.; Deutschbein, T.; Dandekar, T.; Fassnacht, M. The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight. Cancers 2019, 11, 1761.

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