Gene partners of the EWSR1 fusion may represent molecularly distinct entities

•We identified 64 unique fusion partners. Rare fusion partners were identified more often in adults than children and included additional members of the ETS and CREB TF families. The remaining RFPs were classified as other transcription factors and non-transcription factors.•Five genes were identified to be altered at a higher prevalence in rare fusion partner tumors including CCNE1, KRAS, MYC, PIK3CA, and RAD21. Pathway enrichment associated alterations in cell cycle control and DNA damage response genes as driving the differences between fusion partners.•Potentially clinically actionable genomic variants were more prevalent in tumors harboring rare fusion partners than common fusions. Commonly altered genes associated with targetability included PIK4CA, CHEK2, ATM, EZH2, and KRAS.