Chimeric Protein-Protein Interaction Networks Reveal Alterations in Cancer-Specific Phenotypes

Chimeric proteins, comprising peptides deriving from the translation of two parental genes, are produced in cancers by chromosomal aberrations. The expressed fusion protein incorporates domains of both parental proteins. Considering discrete protein domains as binding sites for specific domains of interacting proteins, we have catalogued the protein interaction networks for more than 11,000 cancer fusions in order to build the Chimeric Protein-Protein-Interactions (ChiPPI). Mapping the influence of fusion proteins on cell metabolism and protein interaction networks reveals that chimeric protein-protein interaction (PPI) networks often lose tumor suppressor proteins, and gain onco-proteins. We compared ChiPPI networks in different cancer phenotypes, e.g. in leukemia/lymphoma, sarcoma and solid tumors finding distinct enrichment patterns for each disease type. While certain pathways are enriched in all three diseases (Wnt, Notch, TGF beta), there are distinct patterns for leukemia (EGF receptor signaling, DNA replication, CCKR signaling), for sarcoma (p53 pathway, CCKR signaling), and solid tumors (FGF and EGF signaling). Finally, we validated the predicted PPI networks using high-throughput transcriptomics and proteomics methods. We found that more than 65% of fusions were confirmed at the unique junction sites and more than 46% of PPI networks were altered in at least two data samples. Thus, the ChiPPI method represents a comprehensive tool for studying the anomaly of skewed cellular networks produced by fusion proteins in different cancer types.