The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease
The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease
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DOI：
10.1210/jc.2015-1453
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发表时间：
2015-07-01
影响因子：
5.8
通讯作者：
Reincke, Martin
中科院分区：
文献类型：
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作者：
Perez-Rivas, Luis G.;Theodoropoulou, Marily;Reincke, Martin
背景：我们最近报道了一小部分库欣病患者腺瘤中泛素特异性蛋白酶 USP8 基因的体细胞突变。目的：确定大量诊断为库欣病的患者中 USP8 突变的患病率以及基因型-表型相关性。设计：我们使用桑格测序对 134 个功能性促肾上腺皮质激素腺瘤和 11 个沉默促肾上腺皮质激素腺瘤进行了回顾性、多中心的遗传分析。在 USP8 突变状态的背景下收集和检查生化和临床特征，并通过功能研究来表征新突变。患者：总共 145 名因产生 ACTH 的垂体腺瘤接受手术的患者。主要结果指标：USP8 的突变状态。生化和临床特征包括性别、诊断时年龄、肿瘤大小、术前和术后激素水平以及合并症。结果：我们在 48 例 (36%) 库欣病患者的垂体腺瘤中发现 USP8 体细胞突变，但在 11 例沉默促肾上腺皮质激素瘤中均未发现。成人患病率高于儿童（41% vs 17%），女性患病率高于男性（43% vs 17%）。患有 USP8 突变腺瘤的成年人比患有野生型病变的成年人更早被诊断出来（36 岁 vs 44 岁）。突变主要发现于10+/-7mm的腺瘤中，并且与术后肾上腺功能不全的发生呈负相关。所有突变均影响 Ser718 或 Pro720 残基，包括五个新发现的改变。突变减少了 USP8 和 14-3-3 之间的相互作用并增强了 USP8 活性。 USP8 突变体减少了永生化 AtT-20 促肾上腺皮质激素瘤细胞中表皮生长因子受体泛素化并诱导 Pomc 启动子活性。结论：USP8 在引起库欣病的腺瘤中经常发生突变，尤其是在年轻时诊断的女性成年患者中。
Context: We have recently reported somatic mutations in the ubiquitin-specific protease USP8 gene in a small series of adenomas of patients with Cushing's disease.Objective: To determine the prevalence of USP8 mutations and the genotype-phenotype correlation in a large series of patients diagnosed with Cushing's disease.Design: We performed a retrospective, multicentric, genetic analysis of 134 functioning and 11 silent corticotroph adenomas using Sanger sequencing. Biochemical and clinical features were collected and examined within the context of the mutational status of USP8, and new mutations were characterized by functional studies.Patients: A total of 145 patients who underwent surgery for an ACTH-producing pituitary adenoma.Main Outcomes Measures: Mutational status of USP8. Biochemical and clinical features included sex, age at diagnosis, tumor size, preoperative and postoperative hormonal levels, and comorbidities.Results: We found somatic mutations in USP8 in 48 (36%) pituitary adenomas from patients with Cushing's disease but in none of 11 silent corticotropinomas. The prevalence was higher in adults than in pediatric cases (41 vs 17%) and in females than in males (43 vs 17%). Adults having USP8mutated adenomas were diagnosed at an earlier age than those with wild-type lesions (36 vs 44 y). Mutations were primarily found in adenomas of 10 +/- 7mmand were inversely associated with the developmentof postoperative adrenal insufficiency. All the mutations affected the residues Ser718 or Pro720, including five new identified alterations. Mutations reduced the interaction between USP8 and 14-3-3 and enhanced USP8 activity. USP8 mutants diminished epidermal growth factor receptor ubiquitination and induced Pomc promoter activity in immortalized AtT-20 corticotropinoma cells.Conclusions: USP8 is frequently mutated in adenomas causing Cushing's disease, especially in those from female adult patients diagnosed at a younger age.