SRF fusion genes in myoid soft tissue tumors

Abstract

Serum response factor (SRF) is a ubiquitously expressed transcription factor that regulates immediate early genes, cytoskeletal organization, and muscle differentiation. Although SRF plays critical roles in development and cell growth, genomic alterations of SRF have long appeared absent in human neoplasms. Recently, however, recurrent SRF gene rearrangements have been identified in a spectrum of soft tissue tumors with myogenic features, including rhabdomyosarcomas, perivascular tumors, inflammatory myofibroblastic tumors, myoepitheliomas and peripheral nerve sheath tumors. This review summarizes current knowledge on SRF fusion genes and their biological and clinical implications. SRF fusions retain the N‐terminal DNA‐binding domain while replacing the native transactivation domain with that of a partner protein, frequently a transcription factor or co‐activator. This structural configuration leads to constitutive activation of SRF and dysregulation of transcriptional programs related to myogenesis, cytoskeleton organization, and, in some cases, inflammatory signaling. SRF ‐rearranged tumors predominantly affect children, usually display low‐grade behavior, and are often cured by complete surgical resection, although rare recurrences and metastases have been reported. Within perivascular myoid neoplasms, SRF ‐rearranged tumors show consistent phenotypic and clinical features, supporting their recognition as a distinct tumor entity, whereas SRF fusions identified in rhabdomyosarcomas and rare isolated cases likely represent separate biological contexts. Understanding SRF fusion‐driven transcriptional dysregulation provides insights into tumorigenesis and may inform future diagnostic and therapeutic strategies in myoid soft tissue neoplasms. © 2026 The Pathological Society of Great Britain and Ireland.