Pathogenesis of Cushing Disease: An Update on the Genetics of Corticotropinomas |
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| Institution: | 1. From Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany;2. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;3. Equal contribution.;1. Division of Endocrinology, Diabetes, and Metabolism, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd (111D), Los Angeles, CA 90073;1. From Maryland Endocrine and Diabetes, Columbia, Maryland.;1. From the Department of Clinical Chemistry, NSW Health Pathology; Newcastle, New South Wales, Australia.;1. From the Division of Endocrinology and Diabetes, The Robert Larner, MD College of Medicine at The University of Vermont, Burlington, Vermont;2. Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island.;1. From the Department of Endocrinology, St. William Harvey Research Institute, Barts, and London School of Medicine, Queen Mary University of London, London, United Kingdom. |
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| Abstract: | Objective: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically.Methods: Literature review.Results: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 (USP8) gene in almost half of Cushing disease tumors.Conclusion: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease.Abbreviations: ACTH = adrenocorticotropic hormone; BRG1 = Brahma-related gene 1; CABLES1 = CDK5 and ABL1 enzyme substrate 1; CD = Cushing disease; CNC = Carney complex; DICER1 = cytoplasmic endoribonuclease III; EGFR = epidermal growth factor receptor; GR = glucocorticoid receptor; IL = interleukin; MEN = multiple endocrine neoplasia; miRNA = microRNA; POMC = proopiomelanocortin; SSTR = somatostatin receptor; USP8 = ubiquitin-specific protease 8 |
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