ECE2018 Oral Communications Clinical practice in endocrine tumours: combining conventional and molecular features (5 abstracts)
Update in the genetic landscape of Cushing’s Disease: TP53 and a new deubiquitinase in spotlight
Silviu Sbiera 1, , Nikita Popov 2, , Isabel Weigand 1 , Jörg Flitsch 4 , Luis Gustavo Perez-Rivas 5 , Lyudmyla Taranets 3 , Elisabeth Graf 6 , Camelia-Maria Monoranu 7 , Wolfgang Saeger 8 , Christian Hagel 8 , Marily Theodoropoulou 5, , Günther Stalla 9 , Sabine Herterich 10 , Cristina L. Ronchi 1, , Timo Deutschbein 1 , Martin Reincke 5 , Tim M. Strom 6, & Martin Fassnacht 1,
1Division of Endocrinology and Diabetes, University Hospital of Würzburg, Würzburg, Germany; 2Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany; 3Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany; 4Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 5Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany; 6Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; 7Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany; 8Institute for Neuropathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 9Clinic for Neuroendocrinology and Andrology, Max Planck Institute for Psychiatry, Munich, Germany; 10Clinical Chemistry and Laboratory Medicine, University Hospital Würzburg, Würzburg, Germany; 11Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK; 12Institute of Human Genetics, Technische Universität München, Munich, Germany; 13Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany.
Introduction: Cushing’s disease (CD) is caused by pituitary tumors hypersecreting adrenocorticotropin (ACTH). Until now somatic mutations in the 14-3-3 binding domain of Ubiquitin Specific Peptidase 8 gene (USP8) were the only recurring, driver mutations and were described in about 40% of the 446 CD samples that have been analysed wordwide. We wanted to assess if other driver mutations might be the pathogenetic cause of CD in those tumors without USP8 mutations.
Methods: We performed next generation exome sequencing in matching tumor and germline DNA from 16 corticotroph tumors causing CD and 2 tumors causing Nelson’s syndrome, all of them negative for USP8 mutations. Hotspot Sanger sequencing was performed in tumor DNA from further 86 CD and 8 Nelson’s tumors. In vitro de-ubiquitination assays were performed in transfected HeLa cells using purified K48- and K63-linked ubiquitin chains.
Results: Exome sequencing revealed TP53 mutations in 4 out of 16 (25%) CD tumors and two in both Nelson’s tumors (100%). Three were missense mutations and three, including those in the Nelson tumors, were frameshift mutations and deletions, and were distributed over the whole sequence of TP53. Furthermore, we found also the point missense mutation c.G1245A(p.M415I) in a new deubiquitinase, the Ubiquitin Specific Peptidase 48 gene (USP48) in three further samples (19%). While all tumors had other co-occuring mutations, TP53 and USP48 mutations were mutually exclusive in our cohort. The USP48 mutation was found in further 10 of the 94 samples analyzed by Sanger sequencing (11%), including one Nelson tumor. This mutation increaseed significantly the deubiquitinating activity of USP48 in vitro both for K48 and K63 ubiquitin chains.
Conclusion: We describe here recurring mutations in TP53 and USP48 genes that associate with CD. TP53 mutations suggest an impaired TP53 function in those tumors. The recurrent mutation USP48 was shown to increase deubiquitinating activity in vitro, similar to those activating USP8 mutations that have been reported in CD.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more