Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease

Abstract

Context:Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed.Objective:We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas.Design and Methods:The USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations.Results:Five different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009).Conclusion:Somatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options.

The USP8 mutational status may predict long‐term remission in patients with Cushing's disease

“…Previous studies have postulated a role for USP8 mutational status as predictor of long‐term remission. Patients with USP8 mutant tumours presented with higher 24‐hours‐UFC levels and impaired ACTH reduction after surgery, and paediatric CD patients with USP8 mutant tumours showed higher recurrence rate . Another study suggested a shorter mean recurrence period in USP8 mutants (months 29 vs 48) in a subset of adult CD patients that recurred .…”

“…At the same time, we have shown higher 24‐hour urinary‐free cortisol (UFC) levels and impaired ACTH reduction after surgery in patients with USP8 mutant tumours, suggesting that they may present with higher rate of recurrence . Indeed, a study on paediatric CD patients reported higher recurrence rate in those with USP8 mutant tumours . However, the impact of the USP8 mutational status on long‐term recurrence in adult CD patients remains inconclusive.…”

Biophysical and structural insight into the USP8/14‐3‐3 interaction

“…This results in an increased activation of EGFR signaling and subsequent induction of proopiomelanocortin (POMC) transcription and ACTH secretion . Mutations in the USP8 gene have been identified in around one‐third of both adult and pediatric population affected by CD and have been connected to a higher rate of tumor recurrence after surgical resection of the pituitary adenomas .…”

“…This results in an increased activation of EGFR signaling and subsequent induction of proopiomelanocortin (POMC) transcription and ACTH secretion [8]. Mutations in Abbreviations ACTH, adrenocorticotropic hormone; CD, Cushing's disease; DUB, deubiquitinating enzyme; EGFR, epidermal growth factor receptor; FP, fluorescence polarization; ITC, isothermal titration calorimetry; PPI, protein-protein interaction; USP8, ubiquitin-specific protease 8. the USP8 gene have been identified in around onethird of both adult and pediatric population affected by CD and have been connected to a higher rate of tumor recurrence after surgical resection of the pituitary adenomas [9,10].…”

Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing’s disease

“…Patients with USP8 mutations from our cohort have been reported elsewhere (Pérez-Rivas et al 2015, Faucz et al 2017). …”