Molecular Signatures of Fusion Proteins in Cancer

Although gene fusions
are recognized as driver mutations in a wide
variety of cancers, the general molecular mechanisms underlying oncogenic
fusion proteins are insufficiently understood. Here, we employ large-scale
data integration and machine learning and (1) identify three functionally
distinct subgroups of gene fusions and their molecular signatures;
(2) characterize the cellular pathways rewired by fusion events across
different cancers; and (3) analyze the relative importance of over
100 structural, functional, and regulatory features of ∼2200
gene fusions. We report subgroups of fusions that likely act as driver
mutations and find that gene fusions disproportionately affect pathways
regulating cellular shape and movement. Although fusion proteins are
similar across different cancer types, they affect cancer type-specific
pathways. Key indicators of fusion-forming proteins include high and
nontissue specific expression, numerous splice sites, and higher centrality
in protein-interaction networks. Together, these findings provide
unifying and cancer type-specific trends across diverse oncogenic
fusion proteins.