"Putting the cart before the horse": an update on promiscuous gene fusions in soft tissue tumors

The ever-increasing availability and affordability of molecular genetic testing has revolutionized our understanding of the pathogenesis and proper classification of soft tissue tumors but has also brought new challenges. As is known, many soft tissue tumors harbor gene fusion events, and while it was initially thought that individual entities would be defined by single, specific fusions, it quickly became clear that some entities could be caused by several different fusion events (e.g., EWSR1::FLI1, EWSR1::ERG, EWSR1:FEV and others in Ewing sarcoma). More recently, it has become apparent that these fusion events themselves are "promiscuous", appearing in more than one discrete entity (e.g., EWSR1::CREB1 in clear cell sarcoma, angiomatoid fibrous histiocytoma and others). This review article will briefly discuss the best known examples of genetic promiscuity, the EWSR1/FUS::ATF1/CREB1 and ETV6::NTRK3 fusions, and more comprehensively cover recently discovered and less well-known examples of genetic promiscuity, including EWSR1::WT1, MALAT1::GLI1, YAP1::TFE3 and fusions involving members of the FET and ETS gene families.