Integrative multi-omics framework identifies phenotypically impactful driver pathways in glioblastoma multiforme

Glioblastoma multiforme (GBM), a highly aggressive brain tumor characterized by molecular heterogeneity, demands integrative approaches to uncover driver pathways and therapeutic targets. Here, we present gtePIDP, a computational framework that systematically integrates multi-omics data to identify Phenotypically Impactful Driver Pathways. By evaluating mutation patterns (coverage/exclusivity) and downstream regulatory cascades, this model maps somatic alterations to phenotypic outcomes using TCGA mutation profiles, expression data, and regulatory networks (transcription factors, microRNAs). Through iterative pruning of candidate driver genes and quantifying resultant perturbations in gene expression and regulatory activities, gtePIDP prioritizes gene sets maximizing mutational significance and phenotypic impact. Our analysis uncovered pivotal GBM driver pathways involving TP53, CDKN2A, MDM2, and RB1, which disrupt key cancer-associated regulators (e.g., oncogenic: NFATC2, MIR-370; tumor-suppressive: MIR-506, MIR-9, FOXJ2), driving dysregulation of angiogenesis, apoptosis, and proliferation. Notably, we identified therapeutic axes such as TP53/MIR185/VEGFA and MDM2/SMAD4/VEGFA, suggesting anti-angiogenic targeting strategies. Furthermore, a PI3K-Akt signaling regulatory module revealed actionable targets (CDKN2A/CREBBP/OSMR and TP53/MIR-9/FGF12) for intervention. By bridging mutational landscapes with transcriptional/epigenetic dysregulation, gtePIDP advances mechanistic driver pathway discovery and prioritizes targets with clinical relevance. This study highlights the power of multi-omics integration to unravel GBM pathogenesis and accelerate precision oncology strategies. Additionally, the gtePIDP framework is readily extendable to other malignancies (such as breast carcinoma (BRCA), ovarian cancer (OV), lung adenocarcinoma (LUAD), etc.), providing a universal computational strategy for pan-cancer biomarker discovery.