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

Autor:	Bujko M; Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Kober P; Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Boresowicz J; Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Rusetska N; Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Paziewska A; Department of Genetics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.; Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland., Dąbrowska M; Department of Genetics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Piaścik A; Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Pękul M; Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Zieliński G; Department of Neurosurgery, Military Institute of Medicine, Warsaw, Poland., Kunicki J; Department of Neurosurgery, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Bonicki W; Department of Neurosurgery, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Ostrowski J; Department of Genetics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.; Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland., Siedlecki JA; Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland., Maksymowicz M; Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.
Jazyk:	angličtina
Zdroj:	European journal of endocrinology [Eur J Endocrinol] 2019 Dec; Vol. 181 (6), pp. 615-627.
DOI:	10.1530/EJE-19-0194
Abstrakt:	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.
Databáze:	MEDLINE
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