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Objective  Pituitary corticotroph adenomas commonly cause Cushing’s disease (CD) but part of these tumours are hormonally inactive (silent corticotroph adenomas, SCA).  USP8  mutations are well-known driver mutations in corticotrophinomas. Differences in transcriptomic profiles between functioning and silent tumours or tumours with different  USP8  status have not been investigated.    Design and methods  Forty-eight patients (28 CD, 20 SCA) were screened for  USP8  mutations with Sanger sequencing. Twenty-four patients were included in transcriptomic profiling with Ampliseq Transcriptome Human Gene Expression Core Panel. The entire patients group was included in qRT-PCR analysis of selected genes expression. Immunohistochemistry was used for visualization of selected protein.    Results  We found  USP8  mutation in 15 patients with CD and 4 SCAs.  USP8  mutations determine molecular profile of the tumours as showed by hierarchical clustering and identification of 1648 genes differentially expressed in  USP8 -mutated and  USP8 -wild-type tumours. Mutations affect many molecular pathways as observed in Gene Set Enrichment analysis.  USP8 -mutated adenomas showed higher level of  POMC ,  CDC25A ,  MAPK4  but lower level of  CCND2 ,  CDK6 ,  CDKN1B  than  USP8 -wt tumours. Eighty-seven genes differentially expressed between CD-related adenomas and SCAs were found, including those involved in cell signalling ( GLI2 ,  DLC1 ,  TBX2 ,  RASSF6 ), cell adhesion ( GJA1 ,  CDH6 ), ion transport ( KCNN4 ,  KCNJ5 ) and GABA signalling ( GABBR2 ,  GABRD ).    Conclusion   USP8  mutations occur in functioning and silent corticotrophinomas. They have pleiotropic effect, not limited to EGFR signalling, and affect expression levels of many genes involved in different pathways. Expression of GABA-related genes  GABBR2 ,  GNAL ,  GABARD  and  KCNJ5  correspond to functional status of the tumours.

USP8 mutations in corticotroph adenomas determine a distinct gene expression profile irrespective of functional tumour status