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.

Background: Chronic complications are the major outcome of type 2 diabetes mellitus progress, which reduce the quality of life of patients, incur heavy burdens to the health care system, and increase diabetic mortality. The aims of this study were to describe the prevalence of chronic complications among urban Chinese type 2 diabetic outpatients; and to analyze the associations between chronic complications and patients' demographics, diabetic related clinical characteristics. Methods: This cross-sectional hospital-based study was carried out in 4 major Chinese cities: - Shanghai, Chengdu, Beijing and Guangzhou. The survey was conducted from March to July in 2007 among 1,524 type 2 diabetic outpatients. The subjects were interviewed face-to-face by trained interviewers using a questionnaire to capture information on demographics, disease presentations and complications. All the subjects were invited to have a HbA1c test free of charge by the standardized method with Bio-Rad Variant II. Results: Of the 1,524 study subjects, 637 (41.8%) were male, and the mean age was 63.3 ± 10.2 years. At least one chronic complication was diagnosed in 792 individuals (52.0%) of the study subjects; 509 (33.4%) presented with macrovascular complications and 528 (34.7%) with microvascular complications. The prevalence of cardiovascular and cerebrovascular conditions, neuropathy, nephropathy, ocular lesions and foot disease were 30.1%, 6.8%, 17.8%, 10.7%, 14.8% and 0.8%, respectively. The prevalence of chronic complications varied between cities, and significantly increased with age and duration of diagnosed diabetes. The mean of HbA1c in diabetic patients with chronic complications was 8.2% ± 1.6% and 63.0% of the subjects with type 2 diabetes related complications had a poor glycemic control with the HbA1c > 7.5%. Conclusions: Chronic complications are highly prevalent among type 2 diabetic outpatients, the glycemic control of diabetic patients with chronic complications was poor, and future efforts should be directed at intensive blood glucose control, strengthening early diagnosis and improving case management to prevent and minimize the occurrence of complications.