Recurrent gain-of-function USP8 mutations in Cushing's disease.
Recurrent gain-of-function USP8 mutations in Cushing's disease.
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库欣病中反复出现功能获得性 USP8 突变。
作者：
库欣氏病，也称为促肾上腺皮质激素（ACTH）分泌性垂体腺瘤（PA），可引起过量皮质醇产生，占促肾上腺皮质激素依赖性库欣氏综合征病例的85%。然而，这种疾病的遗传改变尚不清楚。在这里，我们进行了全外显子组测序的DNA来自12个ACTH分泌的PA和匹配的血液样本，揭示了三种类型的体细胞突变的候选基因，USP 8（编码泛素特异性蛋白酶8），专门在外显子14中的8个12 ACTH分泌的PA。我们通过桑格测序进一步评估了另外258个PA中的体细胞USP 8突变。靶向测序进一步鉴定了108例ACTH分泌型PA中的67例（62.04%）共17种USP 8变异。然而，在其他类型的PA中未检测到这些突变（n = 150）。这些突变在USP 8的14-3-3结合基序内聚集，破坏USP 8和14-3-3蛋白之间的相互作用，导致保护EGFR免受溶酶体降解的能力提高。因此，具有突变的USP 8的PA显示出更高的EGFR表达发生率、升高的EGFR蛋白丰度和编码ACTH前体的POMC的mRNA表达水平。与野生型PA相比，具有突变的USP 8的PA在尺寸上显著更小，并且具有更高的ACTH产量。在手术切除的原发性USP 8突变肿瘤细胞中，USP 8敲低或阻断EGFR有效地减弱ACTH分泌。总之，体细胞功能获得性USP 8突变是常见的，并导致库欣病中ACTH过度产生。抑制USP 8或EGFR有望用于治疗USP 8突变的促肾上腺皮质激素腺瘤。我们的研究突出了潜在的功能突变基因在库欣病，并提供了深入了解这种疾病的治疗。
Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.
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