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Adriana Albani Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Luis Gustavo Perez-Rivas Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Sicheng Tang Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Julia Simon Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Kristin Elisabeth Lucia Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Paula Colón-Bolea Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Jochen Schopohl Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Sigrun Roeber Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany

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Michael Buchfelder Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany

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Roman Rotermund Department of Neurosurgery, Universitätskrankenhaus Hamburg-Eppendorf, Hamburg, Germany

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Jörg Flitsch Department of Neurosurgery, Universitätskrankenhaus Hamburg-Eppendorf, Hamburg, Germany

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Jun Thorsteinsdottir Neurochirurgische Klinik und Poliklinik, LMU Klinikum, Munich, Germany

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Jochen Herms Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany

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Günter Stalla Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
Medicover Neuroendocrinology, Munich, Germany

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Martin Reincke Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Marily Theodoropoulou Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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tumours carry somatic mutations in the ubiquitin-specific protease 8 ( USP8 ) gene ( Ma et al. 2015 , Perez-Rivas et al. 2015 , Reincke et al. 2015 , reviewed in Sbiera et al. 2019 ). Studies reported USP8- mutant tumours to be smaller in size

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Donatella Treppiedi Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Genesio Di Muro Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Giusy Marra Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Anna Maria Barbieri Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Federica Mangili Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Rosa Catalano Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Andreea Serban Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy

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Emanuele Ferrante Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy

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Marco Locatelli Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy

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Andrea G Lania Humanitas Clinical and Research Center IRCCS, Endocrinology, Diabetology and Medical Andrology Unit, Milan, Italy
Department of Biomedical Sciences, Humanitas University, Milan, Italy

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Maura Arosio Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy

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Anna Spada Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Erika Peverelli Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Giovanna Mantovani Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy

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identification of gain-of-function somatic mutations in the USP8 gene showing a peculiar specificity for corticotropinomas ( Reincke et al. 2015 ). In this context, USP8 mutations lead to enhanced deubiquitination of EGF receptor (EGFR) and consequent

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Luis G Perez-Rivas Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Andrea Oßwald Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Thomas Knösel Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany

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Kristin Lucia Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany

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Christian Schaaf Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany

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Michael Hristov Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany

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Julia Fazel Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Thomas Kirchner Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany

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Felix Beuschlein Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Martin Reincke Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Marily Theodoropoulou Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany

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treatment ( Terzolo et al. 2001 ). The mechanisms underlying the ectopic production of ACTH are still not well understood. Recently, we and others have reported that the gene coding for the human ubiquitin-specific protease 8 ( USP8 ) is recurrently

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Giampaolo Trivellin Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Ricardo R Correa Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
Endocrinology Training Programs, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Maria Batsis Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
Endocrinology Training Programs, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Fabio R Faucz Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Prashant Chittiboina Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Ivana Bjelobaba Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Darwin O Larco Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

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Martha Quezado Laboratory of Pathology, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Adrian F Daly Department of Endocrinology and Clinical Genetics, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium

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Stanko S Stojilkovic Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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T John Wu Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

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Albert Beckers Department of Endocrinology and Clinical Genetics, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium

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Maya B Lodish Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
Endocrinology Training Programs, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Constantine A Stratakis Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
Endocrinology Training Programs, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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-Price 2009 ). Although germline mutations in genes such as MEN1 , CDKIs, and AIP , and somatic mutations in USP8 have been identified in patients with CD, for many corticotropinomas the molecular pathways involved in their pathogenesis remain unknown

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Chiara Villa Department of Neuropathology, Hôpital Universitaire Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France
Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes-Université de Paris, Paris, France

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Bertrand Baussart Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes-Université de Paris, Paris, France
Department of Neurosurgery, Hôpital Universitaire Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France

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Guillaume Assié Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes-Université de Paris, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin APHP, Paris, France

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Gerald Raverot Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France
Lyon 1 University, Villeurbanne, France
Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France

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Federico Roncaroli Geoffrey Jefferson Brain Research Centre, Division of Neuroscience, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

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USP8 status ( Reincke et al. 2015 , Neou et al. 2020 ), and two subtypes of somatotroph tumours exist when combining transcriptome and GNAS status ( Spada et al. 1990 , Neou et al. 2020 ), which respectively show ubiquitous TPIT and PIT1

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Sylvia L Asa Department of Pathology, The Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada

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Walter Kucharczyk Department of Medical Imaging, The Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada

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Shereen Ezzat Department of Medicine, The Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada

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tumors are often more subtle, and although not silent, have been described as ‘whispering’ ( Asa 2011 ). Mutations in the ubiquitin-specific peptidase USP8 ( Ma et al. 2015 , Reincke et al. 2015 , Hayashi et al. 2016 ) have been identified in

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Laura C Hernández-Ramírez Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Ryhem Gam Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada

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Nuria Valdés Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain

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Maya B Lodish Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Nathan Pankratz Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Aurelio Balsalobre Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada

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Yves Gauthier Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada

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Fabio R Faucz Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Giampaolo Trivellin Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Prashant Chittiboina Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA

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John Lane Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Denise M Kay Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, New York, USA

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Aggeliki Dimopoulos Division of Intramural Population Health Research, Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Stephan Gaillard Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France
Department of Neurosurgery, Hôpital Foch, Suresnes, France

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Mario Neou Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France

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Jérôme Bertherat Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France
Service d’Endocrinologie, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

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Guillaume Assié Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France
Service d’Endocrinologie, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

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Chiara Villa Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France
Department of Pathological Cytology and Anatomy, Hôpital Foch, Suresnes, France
Department of Endocrinology, CHU de Liège, University of Liège, Liège, Belgium

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James L Mills Division of Intramural Population Health Research, Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Jacques Drouin Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada

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Constantine A Stratakis Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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, the germline abnormalities leading to corticotroph cell tumorigenesis remain largely unknown. On the other hand, somatic mutations in the USP8 gene hotspot are highly prevalent among corticotropinomas in adult and pediatric patients, but they have

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Isadora Pontes Cavalcante Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Anna Vaczlavik Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Ludivine Drougat Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Claudimara Ferini Pacicco Lotfi Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

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Karine Perlemoine Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Christopher Ribes Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Marthe Rizk-Rabin Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Eric Clauser Université de Paris, PARCC, INSERM, Paris, France

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Maria Candida Barisson Villares Fragoso Adrenal Unit, Hormone and Molecular Genetic Laboratory/LIM42, Hospital of Clinics, School of Medicine, University of São Paulo, São Paulo, Brazil

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Jérôme Bertherat Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, APHP, Cochin Hospital, Paris, France

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Bruno Ragazzon Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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, recent studies highlight the growing evidences of the ubiquitination/proteasome system alterations in endocrine and more specifically adrenal and pituitary tumors causing Cushing syndrome development. While the ubiquitin-specific protease 8 (USP8) gene is

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Anna Angelousi Department of Pathophysiology, Sector of Endocrinology, National & Kapodistrian University of Athens, Athens, Greece

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Georgios K Dimitriadis Division of Translational and Experimental Medicine, University of Warwick Medical School, Clinical Sciences Research Laboratories, Coventry, UK

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Georgios Zografos Third Department of Surgery, Athens General Hospital “Georgios Gennimatas”, Athens, Greece

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Svenja Nölting Department of Internal Medicine II, Campus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany

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Gregory Kaltsas Department of Pathophysiology, Sector of Endocrinology, National & Kapodistrian University of Athens, Athens, Greece
Division of Translational and Experimental Medicine, University of Warwick Medical School, Clinical Sciences Research Laboratories, Coventry, UK
Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK

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Ashley Grossman Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK

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therapy for ACTH-adenomas, demonstrating promising in vitro results ( Fukuoka et al. 2011 ). Recently, an exhaustive exome-wide screening has led to the identification of somatic mutations in the ubiquitin-specific protease 8 (USP8) in ACTH

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Catalina Simion Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, 4645 2nd Avenue, Sacramento, California 95817, USA

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Maria Elvira Cedano-Prieto Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, 4645 2nd Avenue, Sacramento, California 95817, USA

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Colleen Sweeney Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, 4645 2nd Avenue, Sacramento, California 95817, USA

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promote lysosomal degradation of MET through interaction of the LRIG1–MET complex with HRS. Furthermore, LRIG1 was identified to be a target of the deubiquitinating enzyme USP8, which was shown to counteract LRIG1 ubiquitination and degradation

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