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Sbiera, S.* ; Perez-Rivas, L.G.* ; Taranets, L.* ; Weigand, I.* ; Flitsch, J.* ; Graf, E. ; Monoranu, C.M.* ; Saeger, W.* ; Hagel, C.* ; Honegger, J.* ; Assié, G.* ; Hermus, A.R.* ; Stalla, G.K.* ; Herterich, S.* ; Ronchi, C.L.* ; Deutschbein, T.* ; Reincke, M.* ; Strom, T.M. ; Popov, N.* ; Theodoropoulou, M.* ; Fassnacht, M.*

Driver mutations in USP8 wild-type Cushing's disease.

Neuro. Oncol. 21, 1273-1283 (2019)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Background. Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.Methods. Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.Results. Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on proopiomelanocortin production and adrenocorticotropic hormone secretion.Conclusions. USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cushing's Disease ; Genome Sequencing ; Driver Mutations ; Usp48 ; Tp53; Ubiquitin-specific Protease; Transsphenoidal Surgery; Pituitary-adenomas; Expression; Gene; Landscape; Remission; Secretion; Outcomes; Braf
ISSN (print) / ISBN 1522-8517
e-ISSN 1523-5866
Journal Neuro-Oncology
Quellenangaben Volume: 21, Issue: 10, Pages: 1273-1283 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)