ECE2015 Oral Communications Pituitary – Clinical (5 abstracts)
The ubiquitin-specific protease 8 gene is frequently mutated in adenomas causing Cushing's disease
Luis Gustavo Pérez Rivas 1 , Marily Theodoropoulou 2 , Francesco Ferraù 3 , Clara Nusser 1 , Kohei Kawaguchi 4 , Constantine Stratakis 5 , Fabio Rueda Faucz 5 , Luiz Eduardo Wildemberg 6 , Guillaume Assié 7 , Rudi Beschorner 8 , Günther Stalla 2 , Michael Buchfelder 10 , Vera Popovic 11 , Jürgen Honneger 9 , Jerôme Bertherat 7 , Monica R Gadelha 6 , Felix Beuschlein 1 , Masayuki Komada 4 , Márta Korbonits 3 & Martin Reincke 1
1Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Bavaria, Germany; 2Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Bavaria, Germany; 3Barts and The London School of Medicine, William Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK; 4Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan; 5Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA; 6Division of Endocrinology, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 7INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche, Institut Cochin, Université Paris Descartes, Paris, France; 8Department of Neuropathology, Institute of Pathology and Neuropathology, Tübingen, Baden‐Wurtemberg, Germany; 9Department of Neurosurgery, Eberhard Karls University Tübingen, Tübingen, Baden‐Wurtemberg, Germany; 10Neurochirurgische Klinik, Klinikum der Universität Erlangen, Erlangen, Bavaria, Germany; 11Clinic of Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, University Clinical Center Belgrade, Belgrade, Serbia.
We have recently reported that somatic mutations in the ubiquitin-specific protease 8 (USP8) are present in corticotropinomas of patients with Cushing’s disease and that these mutations reduced the interaction with 14-3-3. Mutant USP8 exhibited higher deubiquitination activity and potentiated EGFR-induced POMC expression (Reincke et al., Nat Genet 2014). To further study the prevalence of these mutations, we have analyzed 134 ACTH-producing corticotropinomas of patients with diagnosed Cushing’s disease from eight different centers by Sanger sequencing.
Results: Somatic mutations in USP8 were found in 48 cases (37%), but not in an additional cohort of 11 ‘silent’ corticotropinomas. The center-specific prevalence ranged from 10.5 to 57% and was lower in pediatric patients (17% vs 41%; P<0.05). Adults having adenomas with USP8 mutations were diagnosed at earlier age (36 years vs 44 years; P<0.05) and had a higher BMI than those with wild type adenomas. Mutations were more frequent in females than in males (43% vs 17%; P<0.005) and were mainly found in adenomas of intermediate size (11.9±6.3 mm). Patients with adenomas containing USP8 mutations also tended to have lower preoperative hormonal levels, although the differences were not significant, and were less prone to develop adrenal insufficiency postoperatively than those with WT tumors (49% vs 71% respectively; P<0.05). Mutations affected the residues Ser718 (52%) or Pro720 (48%). In addition, we identified five new alterations: one missense substitution and four in-frame deletions of several amino acids. They reduced the interaction between USP8 and 14-3-3, increased USP8 cleavage and enhanced its activity. USP8 mutants diminished EGFR ubiquitination and consequently impaired its lysosomal degradation. Furthermore, mutant USP8 proteins enhanced EGFR-induced POMC promoter activity in immortalized AtT20 corticotropinoma cells.
In conclusion, our data highlight the prevalence of USP8 mutations in Cushing’s disease and link these alterations to female adult patients with younger age.
Disclosure: The study was supported by the Else Kröner-Fresenius-Stiftung (grant number 2012_A103 to M Reincke) and the Ministry of Education, Culture, Science and Technology of Japan (grant number 24112003 to M K). M Theodoropoulou is supported by the German Federal Ministry of Education.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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