Unraveling the Network Signatures of Oncogenicity in Virus–Human Protein–Protein Interactions

Background: Climate change, urbanization, and global mobility increase the risk of emerging infectious diseases with pandemic potential. There is a need for rapid methods that can assess their long-term effects on human health. In silico approaches are particularly suited to study processes that may manifest years later, under the assumption that perturbed biomolecular interactions underlie these outcomes. Here we focus on viral oncogenicity—the ability of viruses to increase cancer risk—which accounts for about 15% of global cancer cases. Methods: We characterize viruses through multilayer representations of protein–protein interaction (PPI) networks reconstructed from the human interactome. Statistical analyses of topological features, combined with interpretable machine learning models, are used to distinguish oncogenic from non-oncogenic viruses and to identify proteins with potential central role in these processes. Results: Our analysis reveals clear statistical differences between the network properties of oncogenic and non-oncogenic viruses. Furthermore, the machine learning approach enables classification of virus–host interaction networks and identification of relevant subsets of proteins associated with oncogenesis. Functional enrichment analysis highlights mechanisms related to viral oncogenicity, including chromatin structure and other processes linked to cancer development. Conclusions: This framework enables virus classification and highlights mechanisms underlying viral oncogenicity, providing a foundation for investigating long-term health effects of emerging pathogens.