目的:泛素特异性肽酶(USP8)的激活突变可增强促肾上腺皮质激素垂体腺瘤的细胞增殖和促肾上腺皮质激素(ACTH)分泌。我们调查了患有功能性促肾上腺皮质激素垂体腺瘤(FCPA)的伊朗人群中的USP8变异状态。此外,进行了系统评价,以彻底探索USP8变体和相关途径在促肾上腺皮质激素腺瘤中的作用,具有FCPA的USP8突变个体的基因型-表型相关性,以及USP8和表皮生长因子受体(EGFR)作为PFCA靶向治疗的潜在作用。
方法:使用Sanger测序对19例PFCA患者的20个组织样本进行遗传分析。此外,使用系统评价和荟萃分析的首选报告项目(PRISMA)指南进行系统文献综述。PubMed,Scopus,科学网,搜索了Cochrane数据库。最后一次搜索是在2023年9月20日对所有数据库进行的。
结果:在我们的系列中,我们发现了两个体细胞突变,包括一个7bp的缺失变体:c.2151_2157delCTCCTCC,p.Ser718GlnfsTer3,和一个错义变体:c.2159C>G,p.外显子14中的Pro720Arg(rs672601311)。系统评价显示35%的促肾上腺皮质激素腺瘤中存在USP8变异,在720个代码区域中频率最高(25%),p.Pro720Arg。关于USP8突变状态对FCPA临床特征和结果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-乙氧基亚氨基9H-茚并(1,2-b)吡嗪-2,3-二甲腈,DUBs-IN-2和RA-9在促肾上腺皮质激素腺瘤的治疗中显示出有希望的结果。
结论:尽管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标,需要更精确的多中心研究,以获得关于表型-基因型相关性的更一致的信息,并开发有效的靶向治疗.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.