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.

We present a case of a primary subcutaneous sarcoma harboring an ATXN1::DUX4 gene fusion in a 52-year-old female, representing to our knowledge the first documented occurrence of this molecular subtype arising in soft tissue. The tumor presented as a painless back mass, clinically mimicking a lipoma. Histologic examination revealed an aggressive neoplasm with round to epithelioid morphology, high mitotic activity (30/2 mm2), 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.