ECEESPE2025 Oral Communications Oral Communications 4: Pituitary, Neuroendocrinology and Puberty Part 1 (6 abstracts)
Multi-omics analysis of USP8 mutated and wild type corticotroph pituitary tumors enhances understanding of tumorigenesis, proliferation, immune response and hormone excess in Cushing’s disease
Alexander Paul 1 , Mario Detomas 1 , Roland Coras 2 , Leon Wehner 1 , Panagiota Arampatzi 3 , Tom Gräfenhan 3 , Fabian Imdahl 3 , Silke Appenzeller 4 , Laura Ölsner 4 , Sabine Herterich 5 , Justus Weber 6 , Jörg Flitsch 7 , Jürgen Honegger 8 , Roman Rotermund 7 , Anna Riester 9 , Michael Buchfelder 10 , Alice Ryba 7 , Camelia Monoranu 11 , Martin Fassnacht 1 , David Tourigny 12 & Silviu Sbiera 1
1University Hospital Würzburg, Department of Internal Medicine I, Division of Endocrinology and Diabetes, Würzburg, Germany; 2University Hospital Erlangen, Insitute of Neuropathology, Erlangen, Germany; 3University of Würzburg, Core Unit Systems Medicine, Würzburg, Germany; 4University of Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, Germany; 5University Hospital Würzburg, Department of Internal Medicine I, Central laboratory, Würzburg, Germany; 6University Hospital Würzburg, Department of Internal Medicine II, Chair in Cellular Immunotherapy, Würzburg, Germany; 7University Hospital Hamburg-Eppendorf, Department of Neurosurgery, Hamburg, Germany; 8University Hospital Tübingen, Department of Neurosurgery, Tübingen, Germany; 9LMU Hospital Munich, Department of Medicine IV, Germany; 10University Hospital Erlangen, Department of Neurosurgery, Erlangen, Germany; 11University of Würzburg, Insitute of Pathology, Würzburg, Germany; 12University of Birmingham, School of Mathematics, Birmingham, United Kingdom
JOINT1294
Cushing’s disease (CD) is a rare disease caused by adrenocorticotropic hormone (ACTH) secreting pituitary tumors. Recurrent mutations in USP8 have been identified as drivers of tumorigenesis in about 40% of cases. However, their direct impact at molecular level remains largely unknown. Therefore, our aim was to unveil the effect of USP8 mutations at chromosomal, genomic, transcriptomic and proteomic levels in patients’ material. We gathered 26 cryo- and 90 formalin-fixed paraffin-embedded (FFPE) tumors from patients with CD and normal pituitaries (3 cryo, 10 FFPE). Mutational status was determined using Sanger sequencing. Chromosomal and genomic changes were studied using whole exome sequencing (WES) and shallow whole genome sequencing (sWGS). Transcriptomic changes were investigated using NanoString® nCounter® RNA analysis and single-nucleus RNA sequencing (snRNA-seq.). Protein expression was evaluated using immunohistochemistry. WES and sWGS identified low copy number variation (CNV) levels for USP8 mutated tumors whereas USP8 WT tumors showed variable CNV with higher CNV levels associated with higher recurrence rates. Immunity targeted nCounter® analysis revealed higher expression of inflammation and immune response transcripts in USP8 wild type (WT) tumors. Consistently, snRNA-seq. confirmed enhanced percentage of T-cells in WT tumors and showed complement activation and higher protein secretion in corticotropes of USP8 mutated tumors. Furthermore, USP8 mutated tumors contained higher percentage of corticotropes in G2M and S cell cycle phases compared to WT tumors and normal anterior pituitaries. Interestingly, protein expression analysis revealed weaker staining of Prostaglandin E receptor PTGER4 and growth arrest regulator GADD45B in USP8 mutated tumors, further indicating differences in cell proliferation. Higher staining of ubiquitin-like modifier SUMO1 and secreted protein Osteopontin were found in both tumor groups compared to normal anterior pituitaries, indicating converging roles in tumor progression. Surprisingly, no significant differences of galanin (GAL) and ACTH staining could be found between the tumor groups, however there was a positive correlation between GAL and ACTH solely in USP8 mutated tumors (r=0.411, P=0.03). In addition, stronger staining of corticotroph marker TBX19 was found in USP8 mutated tumors. As both GAL and TBX19 are known regulators of ACTH expression, these findings indicate distinct mechanisms of ACTH regulation in CD tumors based on mutational status, despite similar tumor ACTH levels. To conclude, our study presents extensive insights into Cushing’s disease, highlighting higher genomic stability and cell proliferation in USP8 mutated tumors, higher immune reaction in USP8 WT tumors and differences in ACTH excess regulation based on mutational status.
Volume 110
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2025 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more