Rosa G. Rebollar-Vega , Julia M. Zuarth-Vázquez , Laura C. Hernández-Ramírez
{"title":"Clinical Spectrum of USP8 Pathogenic Variants in Cushing's Disease","authors":"Rosa G. Rebollar-Vega , Julia M. Zuarth-Vázquez , Laura C. Hernández-Ramírez","doi":"10.1016/j.arcmed.2023.102899","DOIUrl":null,"url":null,"abstract":"<div><p><span><span><span>Cushing's disease<span> (CD) is a life-threatening condition with a challenging diagnostic process and scarce treatment options. CD is caused by usually benign adrenocorticotrophic hormone (ACTH)-secreting pituitary </span></span>neuroendocrine tumors (PitNETs), known as </span>corticotropinomas. These tumors are predominantly of sporadic origin, and usually derive from the monoclonal expansion of a mutated cell. Somatic activating variants located within a hotspot of the </span><em>USP8</em> gene are present in 11–62% of corticotropinomas, making <em>USP8</em><span> the most frequent genetic driver of corticotroph neoplasia. In contrast, other somatic defects such as those affecting the glucocorticoid receptor gene (</span><em>NR3C1</em>), the <em>BRAF</em> oncogene, the deubiquitinase-encoding gene <em>USP48</em>, and <em>TP53</em><span> are infrequent. Moreover, patients with familial tumor<span> syndromes, such as multiple endocrine neoplasia<span>, familial isolated pituitary adenoma, and DICER1 rarely develop corticotropinomas. One of the main molecular alterations in </span></span></span><em>USP8</em><span><span>-driven tumors is an overactivation of the epidermal growth factor receptor (EGFR) signaling pathway, which induces </span>ACTH production. Hotspot </span><em>USP8</em> variants lead to persistent <em>EGFR</em><span> overexpression, thereby perpetuating the hyper-synthesis of ACTH. More importantly, they condition a characteristic transcriptomic signature that might be useful for the clinical prognosis of patients with CD. Nevertheless, the clinical phenotype associated with </span><em>USP8</em><span> variants is less well defined. Hereby we discuss the current knowledge on the molecular pathogenesis and clinical picture associated with </span><em>USP8</em> hotspot variants. We focus on the potential significance of the <em>USP8</em> mutational status for the design of tailored clinical strategies in CD.</p></div>","PeriodicalId":8318,"journal":{"name":"Archives of Medical Research","volume":null,"pages":null},"PeriodicalIF":4.7000,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Medical Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0188440923001376","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 1
Abstract
Cushing's disease (CD) is a life-threatening condition with a challenging diagnostic process and scarce treatment options. CD is caused by usually benign adrenocorticotrophic hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs), known as corticotropinomas. These tumors are predominantly of sporadic origin, and usually derive from the monoclonal expansion of a mutated cell. Somatic activating variants located within a hotspot of the USP8 gene are present in 11–62% of corticotropinomas, making USP8 the most frequent genetic driver of corticotroph neoplasia. In contrast, other somatic defects such as those affecting the glucocorticoid receptor gene (NR3C1), the BRAF oncogene, the deubiquitinase-encoding gene USP48, and TP53 are infrequent. Moreover, patients with familial tumor syndromes, such as multiple endocrine neoplasia, familial isolated pituitary adenoma, and DICER1 rarely develop corticotropinomas. One of the main molecular alterations in USP8-driven tumors is an overactivation of the epidermal growth factor receptor (EGFR) signaling pathway, which induces ACTH production. Hotspot USP8 variants lead to persistent EGFR overexpression, thereby perpetuating the hyper-synthesis of ACTH. More importantly, they condition a characteristic transcriptomic signature that might be useful for the clinical prognosis of patients with CD. Nevertheless, the clinical phenotype associated with USP8 variants is less well defined. Hereby we discuss the current knowledge on the molecular pathogenesis and clinical picture associated with USP8 hotspot variants. We focus on the potential significance of the USP8 mutational status for the design of tailored clinical strategies in CD.
期刊介绍:
Archives of Medical Research serves as a platform for publishing original peer-reviewed medical research, aiming to bridge gaps created by medical specialization. The journal covers three main categories - biomedical, clinical, and epidemiological contributions, along with review articles and preliminary communications. With an international scope, it presents the study of diseases from diverse perspectives, offering the medical community original investigations ranging from molecular biology to clinical epidemiology in a single publication.