Abstract
SummaryGene fusions are common cancer-causing mutations, but the molecular principles by which fusion protein products affect interaction networks and cause disease are not well understood. Here, we perform an integrative analysis of the structural, interactomic, and regulatory properties of thousands of putative fusion proteins. We demonstrate that genes that form fusions (i.e., parent genes) tend to be highly connected hub genes, whose protein products are enriched in structured and disordered interaction-mediating features. Fusion often results in the loss of these parental features and the depletion of regulatory sites such as post-translational modifications. Fusion products disproportionately connect proteins that did not previously interact in the protein interaction network. In this manner, fusion products can escape cellular regulation and constitutively rewire protein interaction networks. We suggest that the deregulation of central, interaction-prone proteins may represent a widespread mechanism by which fusion proteins alter the topology of cellular signaling pathways and promote cancer.
Highlights
Fusion genes are hybrid genes formed from two previously independent parent genes
We mapped 2,699 distinct fusion proteins derived from 3,279 genes
Genes that form fusions (‘‘parent genes’’) are enriched for functions related to translation, mRNA splicing, and the cell cycle, and for protein classes related to translation, acetyltransferase activity, and the binding of actin, chromatin, and RNA (Table S1)
Summary
Fusion genes are hybrid genes formed from two previously independent parent genes. Historically, gene fusions have been viewed as common driver mutations in malignancies associated with blood, lymph, and bone marrow tissue, but are becoming increasingly recognized as important players in solid tumors (Mertens et al, 2015a, 2015b; Yoshihara et al, 2015). Translocation-induced gene fusions are found in about 90% of all lymphomas and over half of all leukemias (Lobato et al, 2008), and the TMPRSS2-ERG fusion is the most frequent genetic aberration in prostate cancer (Nam et al, 2007). In accord with their important role in oncogenesis, fusion transcripts and proteins have been utilized in many areas of clinical care, from biomarker development and diagnostics to acting as therapeutic targets (Kumar-Sinha et al, 2015; Mertens et al, 2015b). Despite some concerns over whether certain putative fusion mRNAs may be artifacts of the sequencing procedure (Yu et al, 2014), the widespread finding of recurrent gene fusions in tumor samples, the clinical utility of an increasing number of gene fusions, and a growing body of literature on fusion protein functionality adds support to their potential for significant biological impact
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