Endocrine Abstracts

Cushing's disease results from uncontrolled ACTH secretion by corticotroph adenomas of the pituitary, resulting in excess cortisol secretion. Numerous previous studies attempted to gain insight into the molecular mechanisms underlying the development of Cushing’s disease, but only few rare mutations have been reported. Recently, an exhaustive exome-wide screening has led us to identify somatic mutations in the ubiquitin-specific protease 8 (USP8) in 36% of adenomas. This gene codes for a protein with deubiquitinase (DUB) activity that inhibits the lysosomal degradation of EGFR. USP8 is tightly regulated by 14-3-3 proteins. Mutated USP8 overrides 14-3-3 control and displays higher DUB activity than the wild-type, therefore increasing EGFR stability and enhancing EGFR-induced POMC transcription and ACTH secretion. Meanwhile, we have generated additional data regarding patients with Nelson’s tumor and the ectopic Cushing’s syndrome. In a second approach we are aiming to classify patients with suspected Cushing’s syndrome using urine and plasma steroid finger prints. These studies are performed in collaboration with the University of Birmingham (W. Arlt) and University of Dresden (G. Eisenhofer). My presentation will show preliminary data of those studies and will close with an outlook of future research outcome, based on the hypothesis, that translational medicine will change diagnosis and therapy of Cushing’s syndrome within the next 5 years.