DUX4 (Double Homeobox 4)

The most common gene translocation had a breakpoint located in exon 20 of the CIC gene and exon 1 of the DUX4 gene; this alteration was found in 83% of all CIC::DUX4 cases we identified. We also performed DNA methylation analysis on seven cases, which was proven to be a reliable method with high sensitivity for clustering CIC-rearranged sarcomas.

Herein, we present a case of intracranial CIC::DUX4 rearrangement diagnosed using DNA methylation classifiers and multiple omics diagnosis techniques. We also document the disease progression after chemoradiation therapy and subsequent in situ recurrence.

Despite the relatively favorable outcomes in BCOR sarcomas, the relapse rate is considerable, whereas pediatric patients with CIC sarcoma typically develop metastatic disease and have poor outcomes. The data provide a prospective foundation for genetically based therapeutic strategies and risk stratification.

DUX4-IGH fusion is relatively common in pediatric B-ALL. Transcriptome sequencing enables sensitive detection of this fusion, aiding precise subtyping and prognostic assessment. Early induction response is suboptimal, but the overall prognosis is favorable.

Our findings indicate that the CIC fusion binding partner may alter overall fusion oncoprotein activity. Implications: These first-generation synthetic tools illuminate partner gene-specific mechanistic biology while providing an unprecedented resource to study CIC-family fusions beyond CIC::DUX4 and allow for the dissection of this rare subgroup of cancers.

Recognition of gene fusion signatures not only enhances diagnostic precision but also opens avenues for targeted therapy in selected cases. Continued molecular investigation and case accumulation are necessary to validate the biological behavior and therapeutic implications of many of these newly recognized entities.

Applying these resources to breast tumor, FSHD, and lymphoblastoid cell line datasets revealed that DUX4 is expressed in both breast tumor and FSHD tissues, whereas DUX4C shows expression only in breast tumors. Differential gene expression and Gene Ontology enrichment analyses further suggested that DUX4C expression is associated with activation of pathways involved in leukocyte differentiation, chemotaxis, and cell migration.

Our unique ZC3H7B::BCOR case involved a young adult with spindle cell morphology, myxoid stroma, and negative BCOR staining, underscoring diagnostic challenges and contributing novel clinicopathologic data on this exceedingly rare subtype. These findings highlight key morphologic and immunophenotypic clues to differentiate URCS subgroups and reinforce the importance of integrated histopathological and molecular evaluation to achieve accurate diagnosis and subclassification.

To our knowledge, this represents the sixth reported case of CIC-FOXO4 sarcoma in the English literature and the first with radiologic description. This case adds to the limited radiologic literature on this rare entity and emphasizes the importance of including CIC-rearranged sarcoma in the differential diagnosis of atypical soft tissue masses.

Importantly, we identified novel single nucleotide variants in DUX4, CSF3R and CREBBP, and fusion transcripts. This study not only reports transcriptional heterogeneity in our Latin American cohort but also supports the implementation of open-source bioinformatic pipelines in resource-limited settings to enhance precision diagnosis and guide personalized treatment.

These findings highlight the broader influence of DUX4 on nuclear RNA dynamics and suggest that HSATII RNA could be a critical mediator of RNA processing regulation. Understanding the impact of HSATII-RNP formation on RNA processing provides insight into the molecular mechanisms underlying FSHD.

Here, we present a doxycycline-inducible CIC::DUX4 chimeric mouse model and a cancer line derived from it, imChCDS, that faithfully recapitulates the molecular, histological, and immunological features of human CDS...Genetical inactivation of CIC::DUX4 or pharmacological inhibition of P300/CBP induces cancer cell cycle arrest, restores MHCI expression, and triggers robust anti-tumor immune responses, thereby transforming the immunologically "cold" CDS microenvironment into a "hot" one and driving tumor regression. Together, these models offer a versatile and physiologically relevant platform to investigate CDS pathogenesis, unravel immune evasion mechanisms, and evaluate emerging therapeutic strategies, including those targeting CIC::DUX4/P300/CBP oncogenic axis.