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Driver mutations in USP8 wild-type Cushing's disease
Silviu Sbiera1,2, Luis Gustavo Perez-Rivas3, Lyudmyla Taranets4
1Department of Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg (UKW), Würzburg, Germany.
Background:
Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.
Methods:
Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.
Results:
Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion.
Conclusions:
USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.
Insights
Mutations in USP48 are common in Cushing's disease tumors without USP8 mutations and increase hormone production. TP53 mutations may also be more frequent in larger tumors.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Cushing's disease (CD) pathogenesis is poorly understood, limiting treatment options.
- Ubiquitin specific peptidase 8 (USP8) mutations cause about half of corticotroph tumors.
- This study investigates CD tumors lacking USP8 mutations.
Purpose of the Study:
- Characterize the molecular landscape of USP8-wild-type corticotroph tumors.
- Identify novel genetic drivers in Cushing's disease.
- Understand the functional impact of identified mutations.
Main Methods:
- Exome sequencing of 18 paired tumor-blood samples with wild-type USP8.
- Sanger sequencing of candidate genes in 175 additional samples.
- In vitro functional assays for characterized variants.
Main Results:
- Recurrent USP48 mutations found in 10.3% of USP8-wild-type tumors.
- USP48 variants increased catalytic activity and enhanced CRH-stimulated hormone secretion.
- TP53 variants identified in 6/18 samples, potentially more frequent in larger tumors.
Conclusions:
- USP48 mutations are frequent in USP8-wild-type CD tumors and enhance hormone production.
- These USP48 variants may activate sonic hedgehog signaling.
- TP53 mutations may be more prevalent in larger CD tumors than previously recognized.