Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran, No. 10, Firoozeh St., Vali-asr Ave., Vali-asr Sq, Tehran, Iran.
Department of Pathology, Firoozgar hospital, Iran University of Medical Sciences, Tehran, Iran.
BMC Endocr Disord. 2024 Jun 11;24(1):86. doi: 10.1186/s12902-024-01619-z.
Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs.
Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases.
In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas.
Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.
已鉴定出泛素特异性肽酶 (USP8) 的激活突变可增强促肾上腺皮质激素（ACTH）分泌和促肾上腺皮质激素细胞增殖。我们研究了伊朗功能性促肾上腺皮质激素垂体腺瘤（FCPA）患者群体中的 USP8 变体状态。此外，还进行了系统评价，以深入探讨 USP8 变体及其相关途径在促肾上腺皮质激素腺瘤中的作用、USP8 突变个体的基因型-表型相关性、USP8 和表皮生长因子受体（EGFR）作为 PFCAs 的靶向治疗的潜在作用。
对 19 例 PFCAs 患者的 20 个组织样本进行了 Sanger 测序的遗传分析。此外，还根据首选报告项目进行了系统的文献综述系统评价和荟萃分析 (PRISMA) 指南。检索了 PubMed、Scopus、Web of Sciences 和 Cochrane 数据库。所有数据库的最后一次搜索是在 2023 年 9 月 20 日进行的。
在我们的系列中，我们发现了两个体细胞突变，包括 7 个碱基对缺失变体：c.2151_2157delCTCCTCC，p. Ser718GlnfsTer3 和错义变体：c.2159C > G，p. Pro720Arg(rs672601311)在第 14 外显子中。系统评价表明 USP8 变体在 35%的促肾上腺皮质激素腺瘤中，720 密码子区域的频率最高（25%），p. Pro720Arg。关于 USP8 突变状态对 FCPAs 临床特征和结局的影响的数据不一致。此外，帕瑞肽以及 EGFR 抑制剂如吉非替尼和拉帕替尼，以及 USP8 抑制剂，包括-ehtyloxyimino9H-indeno（1,2-b）pyrazine-2,3-dicarbonitrile、DUBs-IN-2 和 RA-9，在治疗促肾上腺皮质激素腺瘤方面显示出有希望的结果。
虽然 USP8-EGFR 系统已被确定为促肾上腺皮质激素肿瘤发生的主要触发因素和靶点，但需要更精确的多中心研究来提供更一致的关于表型-基因型相关性的信息，并开发有效的靶向治疗方法。
