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Schlagwörter:
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Zusammenfassung:
CONTEXT: We have recently reported somatic mutations in the
ubiquitin-specific protease USP8 gene in a small series of adenomas of
patients with Cushing's disease.
OBJECTIVE: To determine the prevalence of USP8 mutations and the
genotype-phenotype correlation in a large series of patients diagnosed
with Cushing's disease.
DESIGN: We performed a retrospective, multicentric, genetic analysis of
134 functioning and 11 silent corticotroph adenomas using Sanger
sequencing. Biochemical and clinical features were collected and
examined within the context of the mutational status of USP8, and new
mutations were characterized by functional studies.
PATIENTS: A total of 145 patients who underwent surgery for an
ACTH-producing pituitary adenoma.
MAIN OUTCOMES MEASURES: Mutational status of USP8. Biochemical and
clinical features included sex, age at diagnosis, tumor size,
preoperative and postoperative hormonal levels, and comorbidities.
RESULTS: We found somatic mutations in USP8 in 48 (36%) pituitary
adenomas from patients with Cushing's disease but in none of 11 silent
corticotropinomas. The prevalence was higher in adults than in pediatric
cases (41 vs 17%) and in females than in males (43 vs 17%). Adults
having USP8-mutated adenomas were diagnosed at an earlier age than those
with wild-type lesions (36 vs 44 y). Mutations were primarily found in
adenomas of 10 ± 7 mm and were inversely associated with the development
of postoperative adrenal insufficiency. All the mutations affected the
residues Ser718 or Pro720, including five new identified alterations.
Mutations reduced the interaction between USP8 and 14-3-3 and enhanced
USP8 activity. USP8 mutants diminished epidermal growth factor receptor
ubiquitination and induced Pomc promoter activity in immortalized AtT-20
corticotropinoma cells.
CONCLUSIONS: USP8 is frequently mutated in adenomas causing Cushing's
disease, especially in those from female adult patients diagnosed at a
younger age.
