库欣病 (CD) 是一种危及生命的疾病，其诊断过程具有挑战性，且治疗选择稀缺。 CD 通常是由良性分泌促肾上腺皮质激素 (ACTH) 的垂体神经内分泌肿瘤 (PitNET) 引起的，称为促肾上腺皮质激素瘤。这些肿瘤主要是散发性的，通常源自突变细胞的单克隆扩增。位于 USP8 基因热点内的体细胞激活变异存在于 11-62% 的促肾上腺皮质激素瘤中，使 USP8 成为促肾上腺皮质激素瘤最常见的遗传驱动因素。相比之下，其他体细胞缺陷，例如影响糖皮质激素受体基因 (NR3C1)、BRAF 癌基因、去泛素酶编码基因 USP48 和 TP53 的缺陷，则很少见。此外，患有家族性肿瘤综合征（例如多发性内分泌肿瘤、家族性孤立性垂体腺瘤和 DICER1）的患者很少发展为促肾上腺皮质激素瘤。 USP8 驱动的肿瘤的主要分子改变之一是表皮生长因子受体 (EGFR) 信号通路的过度激活，从而诱导 ACTH 的产生。热点 USP8 变异导致 EGFR 持续过度表达，从而使 ACTH 的过度合成永久化。更重要的是，它们调节了特征性转录组学特征，可能对 CD 患者的临床预后有用。然而，与 USP8 变异相关的临床表型尚不明确。在此，我们讨论了与 USP8 热点变异相关的分子发病机制和临床情况的当前知识。我们在 CD 中重点关注 USP8 突变状态对于设计定制临床策略的潜在意义。版权所有 © 2023。由 Elsevier Inc. 出版。

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.Copyright © 2023. Published by Elsevier Inc.