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Driver mutations in USP8 wild-type Cushing's disease.

Silviu Sbiera^1,2, Luis Gustavo Perez-Rivas³, Lyudmyla Taranets⁴

¹Department of Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg (UKW), Würzburg, Germany.

|June 22, 2019

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Summary

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.

Keywords:

Cushing’s disease TP53 USP48 driver mutations genome sequencing

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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.