Abstract
Background/Objectives: Lower-grade gliomas (LGGs) are a biologically and clinically heterogeneous group of brain tumors, for which molecular stratification plays essential role in diagnosis, prognosis, and therapeutic decision-making. Conventional unimodal classifiers do not necessarily describe cross-layer regulatory dynamics which entail the heterogeneity of glioma. Methods: This paper presents a protein-protein interaction (PPI)-informed hybrid model that combines multi-omics profiles, including RNA expression, DNA methylation, and microRNA expression, with a Graph Attention Network (GAT), Random Forest (RF), and logistic stacking ensemble learning. The proposed model utilizes ElasticNet-based feature selection to obtain the most informative biomarkers across omics layers, and the GAT module learns the biologically significant topological representations in the PPI network. The Synthetic Minority Over-Sampling Technique (SMOTE) was used to mitigate the class imbalance, and the model performance was assessed using a repeated five-fold stratified cross-validation approach using the following performance metrics: accuracy, precision, recall, F1-score, ROC-AUC, and AUPRC. Results: The findings illustrate that a combination of multi-omics data increases subtype classification rates (up to 0.984 ± 0.012) more than single-omics methods, and DNA methylation proves to be the most discriminative modality. In addition, analysis of interpretability using attention revealed the major subtype-specific biomarkers, including UBA2, LRRC41, ANKRD53, and WDR77, that show great biological relevance and could be used as diagnostic and therapeutic tools. Conclusions: The proposed multi-omics based on a biological and explainable framework provides a solid computational approach to molecular stratification and biomarker identification in lower-grade glioma, bridging between predictive power, biological clarification, and clinical benefits.