A primary subcutaneous sarcoma with ATXN1::DUX4 fusion: the first report in soft tissue and further evidence for a CIC/ATXN1 pathway-altered sarcoma family.

), geographic necrosis, and focal myxoid stroma. Immunohistochemically, the tumor showed focal strong ALK (D5F3) expression, partial membranous CD99 positivity, and focal nuclear WT1 expression (with diffuse non-specific cytoplasmic staining). A broad panel of other lineage-specific markers was negative, while INI1 and BRG1 expression was retained. ALK and CIC break-apart fluorescence in situ hybridization (FISH) were negative. Targeted RNA sequencing identified an in-frame ATXN1::DUX4 fusion (exon 8 to exon 1), which retains the AXH domain of ATXN1. The fusion was validated by RT-PCR and Sanger sequencing, and an ATXN1 break-apart FISH assay confirmed rearrangement in 65% of tumor nuclei. DNA methylation analysis demonstrated that the tumor clustered with CIC-rearranged sarcomas.The patient experienced local recurrence five months after resection despite adjuvant chemotherapy. Recent functional studies have demonstrated that ATXN1::DUX4 activates CIC target genes in an AXH domain-dependent manner, supporting its classification within the emerging family of CIC/ATXN1 pathway-altered sarcomas. This case expands the anatomic spectrum of ATXN1::DUX4-fusion sarcomas and provides further epigenetic evidence supporting their inclusion within the CIC/ATXN1 pathway-altered sarcoma family.