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The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895825/ https://www.ncbi.nlm.nih.gov/pubmed/31717455 http://dx.doi.org/10.3390/cancers11111761 |
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author | Sbiera, Silviu Kunz, Meik Weigand, Isabel Deutschbein, Timo Dandekar, Thomas Fassnacht, Martin |
author_facet | Sbiera, Silviu Kunz, Meik Weigand, Isabel Deutschbein, Timo Dandekar, Thomas Fassnacht, Martin |
author_sort | Sbiera, Silviu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6895825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68958252019-12-24 The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight Sbiera, Silviu Kunz, Meik Weigand, Isabel Deutschbein, Timo Dandekar, Thomas Fassnacht, Martin Cancers (Basel) Article 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. MDPI 2019-11-08 /pmc/articles/PMC6895825/ /pubmed/31717455 http://dx.doi.org/10.3390/cancers11111761 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sbiera, Silviu Kunz, Meik Weigand, Isabel Deutschbein, Timo Dandekar, Thomas Fassnacht, Martin The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight |
title | The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight |
title_full | The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight |
title_fullStr | The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight |
title_full_unstemmed | The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight |
title_short | The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight |
title_sort | new genetic landscape of cushing’s disease: deubiquitinases in the spotlight |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895825/ https://www.ncbi.nlm.nih.gov/pubmed/31717455 http://dx.doi.org/10.3390/cancers11111761 |
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