Clinical Spectrum of USP8 Pathogenic Variants in Cushing's Disease.
Arch Med Res
; 54(8): 102899, 2023 12.
Article
em En
| MEDLINE
| ID: mdl-37925320
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Adenoma
/
Hipersecreção Hipofisária de ACTH
/
Adenoma Hipofisário Secretor de ACT
Limite:
Humans
Idioma:
En
Revista:
Arch Med Res
Assunto da revista:
MEDICINA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
México