期刊
NUCLEIC ACIDS RESEARCH
卷 45, 期 12, 页码 7094-7105出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx423
关键词
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资金
- Spanish Ministry of Economy, Industry and Competitiveness (MEIC) [BFU2015-71241-R]
- European Regional Development Fund (ERDF)
- Instituto de Salud Carlos III (ISCIII), Strategic Action in Health [PT13/0001/0030]
- Israel Cancer Association (ICA) fund
- VaTaT Postdoctoral Fellowship [22351, 20027, 26912]
- Joint BSC-CRG-IRB Programme in Computational Biology
- ICA [e-cancer-diagnosis]
Fusion proteins, comprising peptides deriving from the translation of two parental genes, are produced in cancer by chromosomal aberrations. The expressed fusion protein incorporates domains of both parental proteins. Using a methodology that treats discrete protein domains as binding sites for specific domains of interacting proteins, we have cataloged the protein interaction networks for 11 528 cancer fusions (ChiTaRS-3.1). Here, we present our novel method, chimeric protein-protein interactions (ChiPPI) that uses the domain-domain co-occurrence scores in order to identify preserved interactors of chimeric proteins. Mapping the influence of fusion proteins on cell metabolism and pathways reveals that ChiPPI networks often lose tumor suppressor proteins and gain oncoproteins. Furthermore, fusions often induce novel connections between non-interactors skewing interaction networks and signaling pathways. We compared fusion protein PPI networks 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 and TGF beta), there are distinct patterns for leukemia (EGFR signaling, DNA replication and CCKR signaling), for sarcoma (p53 pathway and CCKR signaling) and solid tumors (FGFR and EGFR signaling). Thus, the ChiPPI method represents a comprehensive tool for studying the anomaly of skewed cellular networks produced by fusion proteins in cancer.
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