USP8 Mutations and Cell Cycle Regulation in Corticotroph Adenomas

Abstract

Corticotroph adenomas frequently harbor somatic USP8 mutations. These adenomas also commonly exhibit underexpression of P27, a cell cycle regulator. The present study aimed to determine the influence of USP8 mutations on clinical features of Cushing's disease and to elucidate the relationship between USP8 mutations and P27 underexpression in these tumors. Retrospective study with 32 patients with Cushing's disease was followed at the Ribeirao Preto Medical School University Hospital. We evaluated the patients' clinical data, the USP8 mutation status and the gene expression of cell cycle regulators P27/CDKN1B, CCNE1, CCND1, CDK2, CDK4, and CDK6 in tumor tissue in addition to the protein expression of P27/CDKN1B. We observed somatic mutations in the exon 14 of USP8 in 31.3% of the patients. Larger tumor size was observed in patients harboring USP8 mutations (p=0.04), with similar rates of remission, age of presentation, salivary cortisol at 23:00 h and after 1 mg dexamethasone, ACTH levels, and early postoperative plasma cortisol. We observed no differences regarding the gene or protein expression of the cell cycle regulators according to USP8 mutation status. In this Brazilian series, the observed frequency of USP8 somatic mutations was similar to that reported in European ancestry populations. Although it was reasonable that USP8 mutations could contribute to cell cycle dysregulation and P27 underexpression in corticotroph adenomas, our data did not confirm this hypothesis. It is possible that increased deubiquitinase activity observed in mutated USP8 might influence other pathways related to cell growth and proliferation.