The EGFRvIII transcriptome in glioblastoma: A meta-omics analysis.

Autor:	Hoogstrate Y; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.; Cancer Computational Biology Center, Erasmus MC, Rotterdam, The Netherlands.; Department of Urology, Erasmus MC, Rotterdam, The Netherlands., Ghisai SA; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands., de Wit M; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands., de Heer I; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands., Draaisma K; Department of Neurosurgery, UMC Utrecht, Utrecht, The Netherlands., van Riet J; Cancer Computational Biology Center, Erasmus MC, Rotterdam, The Netherlands., van de Werken HJG; Cancer Computational Biology Center, Erasmus MC, Rotterdam, The Netherlands.; Department of Urology, Erasmus MC, Rotterdam, The Netherlands.; Department of Immunology, Erasmus MC, Rotterdam, The Netherlands., Bours V; Department of Human Genetics, Université de Liège, Liège, Belgium., Buter J; Department of Oncology, VU University Medical Center, Amsterdam, The Netherlands., Vanden Bempt I; Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium., Eoli M; Unit of Molecular Neuro-Oncology, Besta-IRCCS, Milan, Italy., Franceschi E; IRCCS Istituto Scienze Neurologiche di Bologna, Nervous System Medical Oncology Department, Bologna, Italy., Frenel JS; Institut de Cancérologie de l'Ouest, Nantes, France., Gorlia T; EORTC Headquarters, Brussels, Belgium., Hanse MC; Department of Neurology, Catharina Hospital, Eindhoven, The Netherlands., Hoeben A; Department of Medical Oncology, Maastricht UMC+, Maastricht, The Netherlands., Kerkhof M; Department of Neurology, Haaglanden Medical Center, The Hague, The Netherlands., Kros JM; Department of Medical Oncology, Erasmus MC, Rotterdam, The Netherlands.; Department of Pathology, Erasmus MC, Rotterdam, The Netherlands., Leenstra S; Department of Neurosurgery, Erasmus MC, Rotterdam, The Netherlands., Lombardi G; Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., Lukacova S; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark., Robe PA; Department of Neurosurgery, UMC Utrecht, Utrecht, The Netherlands., Sepulveda JM; Hospital Universitario 12 de Octubre, Madrid, Spain., Taal W; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands., Taphoorn M; Department of Neurology, Haaglanden Medical Center, The Hague, The Netherlands., Vernhout RM; Department of Radiotherapy, Erasmus MC, Rotterdam, The Netherlands., Walenkamp AME; Department of Medical Oncology, UMC Groningen, Groningen, The Netherlands., Watts C; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom., Weller M; Department of Neurology, University Hospital Zurich, Zurich, Switzerland., de Vos FYF; Department of Medical Oncology, UMC Utrecht, Utrecht, The Netherlands., Jenster GW; Department of Urology, Erasmus MC, Rotterdam, The Netherlands., van den Bent M; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands., French PJ; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2022 Mar 12; Vol. 24 (3), pp. 429-441.
DOI:	10.1093/neuonc/noab231
Abstrakt:	Background: EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being among its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signaling compared with wildtype EGFR. Methods: To better understand the oncogenic role of EGFRvIII, we leveraged 4 large datasets into 1 large glioblastoma transcriptome dataset (n = 741) alongside 81 whole-genome samples from 2 datasets. Results: The EGFRvIII/EGFR expression ratios differ strongly between tumors and range from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII-positive and -negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (P = .007), which may point toward crosstalk between these pathways. EGFRvIII-expressing tumors have an upregulation of "classical" subtype genes compared to those with EGFR-amplification only (P = 3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference toward the 3'-end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. Conclusions: These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumors. (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu