The EGFRvIII transcriptome in glioblastoma: A meta-omics analysis. Issue 3 (5th October 2021)

• Record Type: Journal Article
• Authors: Hoogstrate, Youri; Ghisai, Santoesha A; de Wit, Maurice; de Heer, Iris; Draaisma, Kaspar; van Riet, Job; van de Werken, Harmen J G; Bours, Vincent; Buter, Jan; Vanden Bempt, Isabelle; Eoli, Marica; Franceschi, Enrico; Frenel, Jean-Sebastien; Gorlia, Thierry; Hanse, Monique C; Hoeben, Ann; Kerkhof, Melissa; Kros, Johan M; Leenstra, Sieger; Lombardi, Giuseppe; Lukacova, Slávka; Robe, Pierre A; Sepulveda, Juan M; Taal, Walter; Taphoorn, Martin; Vernhout, René M; Walenkamp, Annemiek M E; Watts, Colin; Weller, Michael; de Vos, Filip Y F; Jenster, Guido W; van den Bent, Martin; French, Pim J;
• Is Part Of: Neuro-oncology. Volume 24:Issue 3(2022)
• Page Start: 429
• Page End: 441
• Publication Date: 2021-10-05
• Subjects: breakpoints -- EGFR -- EGFRvIII -- glioblastoma -- RNA-seq; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab231
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: 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.