Novel ACTB::FER Promoter Swap Fusion Characterizes Rare Superficial Myoid/Myofibroblastic Tumors.

Pediatric fibroblastic, myofibroblastic, and myoid tumors encompass several entities, many with characteristic gene fusions that are now emerging as molecularly defined tumor groups. Here, we present two cases of spindle cell neoplasms with novel ACTB::FER promoter swap fusions. Both tumors presented in the extremities of pediatric patients (9-year-old and 6-year-old females) as superficial skin nodules with slow growth. Histologically, both tumors showed monomorphic spindle cell proliferation in short fascicles, but without significantly increased mitotic activity, high-grade atypia, or necrosis. Both cases showed diffuse positivity for SMA with patchy desmin expression. RNA sequencing confirmed fusion breakpoints, revealing transcriptional upregulation of FER. Neither patient has had evidence of interval growth or recurrence to date. While the biological significance of ACTB::FER fusions remains unclear, their recurrence and the absence of other clear oncogenic drivers suggest a distinct molecular pathway that may define a novel entity. Fusions of ACTB and FER genes with different partners have been observed in rare aggressive mesenchymal tumors; however, the ACTB::FER promoter swap fusion is currently unrecognized in soft tissue tumors. We report the first two cases of soft tissue tumors harboring ACTB::FER fusions and expand the molecular spectrum of mesenchymal tumors with kinase gene alterations. Further, we highlight the importance of target-agnostic approaches for the detection of rare kinase fusions, which may not be included on targeted next-generation sequencing panels.