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Trancriptome analysis of tumor tissue to search for the associations between USP8 mutation status, molecular markers of pituitary adenomas, and clinical, and diagnostic parametres of Cushing disease

ABSTRACT: In this work we employed the comprehensive evaluation of clinical data of the cohort of CD patients along with the sequencing of 14 exon of USP8 to estimate the prevalence of USP8 mutations in our cohort and transcriptome analysis of tumor tissue to search for the associations between USP8 mutation status, molecular markers of pituitary adenomas, and clinical and diagnostic parameters of Cushing’s syndrome including hormonal secretion, tumor size, aggressiveness, and SSRT2/SSRT5 expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263206 | GEO | 2024/04/11

REPOSITORIES: GEO

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Differential microRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes

Project description:Background: USP8 mutations are the most common driver changes in corticotroph pituitary tumors. They have direct effect on cells’ proteome through disturbance of ubiquitination process and also influence gene expression. The aim of this study was to compare microRNA profiles in USP8- mutated and wild-type tumors and determine the probable role of differential microRNA expression by integrative microRNA and mRNA analysis. Methods: Patients with Cushing’s disease (n = 28) and silent corticotroph tumors (n = 20) were included. USP8 mutations were identified with Sanger sequencing. MicroRNA and gene expression was determined with next-generation sequencing. Results: USP8-mutated patients with Cushing’s disease showed higher rate of clinical remission and trend towards lower tumor volume than wild-type patients. Comparison of microRNA profiles of USP8-mutated and wild-type tumors revealed 68 differentially expressed microRNAs. Their target genes were determined by in silico prediction and microRNA/mRNA correlation analysis. GeneSet Enrichment analysis of putative targets showed that the most significantly overrepresented genes are involved in protein ubiquitination-related processes. Only few microRNAs influence the expression of genes differentially expressed between USP8-mutated and wild-type tumors. Conclusions: Differences in microRNA expression in corticotropinomas stratified according to USP8 status reflect disturbed ubiquitination processes, but do not correspond to differences in gene expression between these tumors.

2021-02-06 | GSE166279 | GEO

Trancriptome analysis of tumor tissue to search for the associations between USP8 mutation status, molecular markers of pituitary adenomas, and clinical, and diagnostic parametres of Cushing disease

Project description:Trancriptome analysis of tumor tissue to search for the associations between USP8 mutation status, molecular markers of pituitary adenomas, and clinical, and diagnostic parametres of Cushing disease

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USP8 Mutations in Pituitary Cushing Adenomas-Targeted Analysis by Next-Generation Sequencing.

Project description:Gain-of-function somatic mutations in the ubiquitin specific protease 8 (USP8) gene have recently been reported as a cause of pituitary adenomas in Cushing disease. Molecular diagnostic testing of tumor tissue may aid in the diagnosis of specimens obtained through therapeutic transsphenoidal surgery; however, for small tumors, availability of fresh tissue is limited, and contamination with normal tissue is frequent. We performed molecular testing of DNA isolated from single formalin-fixed and paraffin-embedded (FFPE) tissue sections of 42 pituitary adenomas from patients with Cushing disease (27 female patients and 15 male patients; mean age at surgery, 42.5 years; mean tumor size, 12.2 mm). By Sanger sequencing, we identified previously reported USP8 missense mutations in six tumors. Targeted next-generation sequencing (NGS) revealed known or previously undescribed missense mutations in three additional tumors (two with two different mutations each), with mutant allele frequencies as low as 3%. Of the nine tumors with USP8 mutations (mutation frequency, 21.4%), seven were from female patients (mutation frequency, 25.9%), and two were from male patients (mutation frequency, 13.3%). Mutant tumors were on average 11.4 mm in size, and patients with mutations were on average 43.9 years of age. The overall USP8 mutation frequency in our cohort was lower than in previously described cohorts, and we did not observe USP8 deletions that were frequent in other cohorts. We demonstrate that testing for USP8 variants can be performed from small amounts of FFPE tissue. NGS showed higher sensitivity for USP8 mutation detection than did Sanger sequencing. Assessment for USP8 mutations may complement histopathological diagnosis.

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USP8 mutations determine genes’ expression profile of pituitary corticotroph adenomas, regardless of tumor functional status.

Project description:The aim of the study was to compare genes’ expression profiles of functioning and silent corticotroph adenomas to investigate possible biological mechanism of different hormone secretion . Since USP8 is the best know driver gene mutated in large proportion of ACTH-omas we intended to verify whether the mutation occurs in SCAs and how it affects transcriptomic profile.

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Transcriptome profiling of wild-type (WT) and USP8 knockout (KO) CT26 cell lines

Project description:USP8 is one of DUBs and is frequently overexpressed or gain-of-function mutated in multiple types of human cancer. Importantly, USP8 has been identified as an immunomodulatory DUB as T cell-specific Usp8 deficiency disrupts regulatory T cell functions, leading to recruiting abundant CD8+ T cells in colons and resulting in the inflammatory bowel disease in mice. However, whether targeting USP8 can enhance anti-tumor immunity has not been reported. To further explore the physiological function of USP8, we performed the transcriptomic analysis to comprehensively understand which signaling pathways are mainly regulated by USP8 in cancer cells. Usp8 WT and KO CT26 cells were harvested for RNA-sequencing (RNA-seq).

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USP8 coordinates ESCRT-mediated membrane repair, xenophagy, and oxidative stress responses during Mycobacterium tuberculosis infection

Project description:We show that USP8 colocalizes with intracellular Mtb, recognizes phagosomal membrane damage, and is required for ESCRT-dependent membrane repair. Furthermore, USP8 regulates the NRF2-dependent antioxidant signature. Taken together, our study shows a central role of USP8 in promoting intracellular growth of Mtb by coordinating phagosomal membrane repair, ubiquitin-driven selective autophagy, and the oxidative stress response.

2024-08-07 | GSE240372 | GEO

FLAG-Ub IP/MS of USP8-depleted cells

Project description:The analysis to identify ubiquitinated proteins increased on endosomes in USP8-depleted cells.

2023-12-17 | PXD042488 | Pride

TMT 6-plex proteome analyisis of USP8-depleted cells

Project description:The analysis to investigate the change in proteome of USP8-depleted cells

2023-12-17 | PXD042490 | Pride

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

Project description: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.We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas.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.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).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.

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USP8 mutations determine genes’ expression profile of pituitary corticotroph adenomas, regardless of tumor functional status.

Project description:USP8 mutations determine genes’ expression profile of pituitary corticotroph adenomas, regardless of tumor functional status.

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