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 ne...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/11/1761 |
| _version_ | 1797708643777380352 |
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| author | Silviu Sbiera Meik Kunz Isabel Weigand Timo Deutschbein Thomas Dandekar Martin Fassnacht |
| author_facet | Silviu Sbiera Meik Kunz Isabel Weigand Timo Deutschbein Thomas Dandekar Martin Fassnacht |
| author_sort | Silviu Sbiera |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T06:24:27Z |
| format | Article |
| id | doaj.art-efbeadb3dec949bc8c96467139eb00f4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:24:27Z |
| publishDate | 2019-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-efbeadb3dec949bc8c96467139eb00f42023-09-03T02:02:14ZengMDPI AGCancers2072-66942019-11-011111176110.3390/cancers11111761cancers11111761The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the SpotlightSilviu Sbiera0Meik Kunz1Isabel Weigand2Timo Deutschbein3Thomas Dandekar4Martin Fassnacht5Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, D-97080 Würzburg, GermanyChair of Medical Informatics, Friedrich-Alexander University of Erlangen-Nürnberg, D-91058 Erlangen, GermanyDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Bioinformatics, Biocenter, University of Würzburg, D-97074 Würzburg, GermanyDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, D-97080 Würzburg, GermanyCushing’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.https://www.mdpi.com/2072-6694/11/11/1761cushing’s diseasepathogenesissomatic mutationsdeubiquitinases |
| spellingShingle | Silviu Sbiera Meik Kunz Isabel Weigand Timo Deutschbein Thomas Dandekar Martin Fassnacht The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight Cancers cushing’s disease pathogenesis somatic mutations deubiquitinases |
| 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 | cushing’s disease pathogenesis somatic mutations deubiquitinases |
| url | https://www.mdpi.com/2072-6694/11/11/1761 |
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