GONet: A Molecular Interaction-Guided Graph Learning Framework for Multi-Omics Cancer Classification.

Integrating multi-omics profiles with molecular interaction networks enables biologically informed representation learning by combining molecular measurements with prior biological knowledge. Although graph neural networks (GNNs) are well suited for modeling molecular interaction networks, existing multi-omics methods often rely on shallow representation learning or incomplete fusion strategies, which fail to fully capture complementary information and complex dependencies across heterogeneous omics layers, resulting in suboptimal performance and limited generalizability in cancer classification tasks. Here, we propose GONet, a hierarchical GNN framework that integrates omics expression profiles, including mRNA, miRNA, and protein data, with molecular interaction networks, where nodes represent omics features and edges represent molecular interactions. GONet learns global omics representations via an autoencoder, captures local structural dependencies using Deep Graph Infomax (DGI), and enhances omics-specific representations through an attention mechanism. A gated fusion module further enables adaptive integration of heterogeneous features, improving cancer subtype and stage classification. GONet was systematically evaluated on 13 publicly available benchmark datasets used in prior studies, covering 10 cancer types, ensuring fair comparison across methods. Across mRNA and miRNA datasets, GONet achieved an average AUROC of 0.9262, outperforming representative GNN- and non-GNN-based methods by 13.77% and 6.35%, respectively. On an independent CPTAC cohort spanning seven cancer types, it improved performance by 25.22% and 13.91%, respectively. Incorporating proteomics further improved cancer stage classification by 5.56%, demonstrating complementary predictive value. Ablation studies confirmed the effectiveness of the DGI-based module. Overall, GONet provides a unified framework for biologically informed multi-omics graph representation learning and cancer classification.