Fig. 2

Whole-exome and transcriptome analysis of EGFR-mutant mouse brain and spinal cord gliomas. a Mutational profile of 17 brain and spinal tumors. Genes are ranked according to the frequency of mutations (indels or SNVs). Known glioma drivers include Trp53 and Nf1, and novel ones found mutated are Sub1 and Tead2. b Copy number profile, left axis shows frequency of larger amplifications and deletions, whereas right axis represents frequency of focal copy number changes; key genes with focal alterations are highlighted. c Gene set enrichment analysis reveals collaborative pathways in EGFR-mutant brain tumors, including oncogenic pathways, stem cell, and epithelial to mesenchymal (EMT)-related pathways. Each line identifies a transcriptomic profile with a Bonferroni-adjusted p value < 0.01. Although not displayed here, spinal tumors are enriched for the same pathways implying conserved molecular mechanisms. d Plot showing stronger upregulation of EGFRvIII mRNA expression (from RNA sequencing) compared with wild-type Egfr in tumors, highlighting the former is the more prominent driver (****p < 0.0001, paired t test; n = 11 brain tumors, n = 10 spinal tumors, relative to wild-type brain, n = 6, and spinal cord, n = 6). Mean expression and standard deviation values are plotted. e Hox gene upregulation in EGFRvIII-brain gliomas. Genes are ranked according to log₂ fold change compared to wild-type brain, Benjamini-Hochberg adjusted p < 1 × 10⁻¹² for each gene. f Heat map showing expression of HOX genes in human GBMs relative to normal brain from three datasets (TCGA, Murat and Sun; n = 542, 80 and 81 GBMs respectively); log₂ fold changes are all significant with Benjamini-Hochberg adjusted p < 0.05, except for “NC” (“no change”). Genes are ranked according to the greatest upregulation in mouse tumors. Heatmap shows upregulation for HOX genes in human GBMs, with no cases of downregulation. g Gene set enrichment analysis (GSEA) plots for EGFRvIII mouse gliomas showing significant positive enrichment for human mesenchymal GBM and negative enrichment for the neural GBM signature (Verhaak dataset); normalized enrichment score (NES) and FDR q value are stated on the plots. There was also weaker positive enrichment for Verhaak human proneural GBM and classical GBM signatures (NES 2.22 and 1.92, FDR q value 0.004 and 0.018 respectively)