Fig. 5: Integrating transcriptomic, proteomic, and DNA methylation profiles of IDH-mutant gliomas.

A We compared transcript and protein expression and promoter DNA methylation of IDH-mutant and IDH-wildtype gliomas. We prioritised mRNA (R) and protein (P) expression levels that directly associated with each other and inversely associated with promoter DNA methylation (M) using the constraints vector (CV) [M = +1, R = −1, P = −1]. At least six IDH-mutant and 90 IDH-wildtype samples were included depending on data type. B Venn diagrams of significant genes found separately in three input datasets (false discovery rate (FDR) < 0.1, Mann-Whitney U-tests). Downregulated genes showed reduced mRNA and protein expression and increased promoter methylation, while upregulated genes showed decreased promoter methylation. C Scatter plot of merged P-values from directional analysis (DPM, Y-axis) and non-directional analysis (Brown, X-axis). Prioritised genes with consistent multi-omics directions are shown on the diagonal or closely below it (blue), while directionally penalised genes are further below the diagonal (red). Unadjusted P-values are shown. D Heatmap of significantly penalised or prioritised top genes (Brown, FDR < 0.001). Prioritised genes were often characterised by high promoter methylation and reduced mRNA and protein expression, while penalised genes often showed high promoter methylation and increased expression. Known cancer genes are listed and coloured as directionally penalised or prioritised. E Venn diagram of enriched pathways from the directional and non-directional analyses (ActivePathways, family-wise error rate (FWER) < 0.05). F Enrichment map of pathways and processes in IDH-mutant glioblastoma. The network shows pathways as nodes that are connected by edges if the corresponding pathways share many genes. Major groups of directionally prioritised or penalised pathways are grouped on the right. G Dot plot of significant genes involved in the gliogenesis process. This process was only detected in the directional analysis as several related genes showed significant and directionally consistent changes. Unadjusted P-values from Mann-Whitney U-tests are shown. Carets show known cancer genes. H Validating the multi-omics analysis of IDH-mutant gliomas in an independent dataset. Functional themes from the discovery dataset (TCGA, CPTAC) and validation dataset (GLASS⁴⁸, Oh et al.⁴⁹) were compared. Known cancer genes were retrieved from COSMIC Cancer Gene Census⁵³ (panels D, G).