Glial Maturation and Immune Landscape Dynamics in MN1::PATZ1 Fusion-Positive CNS Tumor Recurrence.

BackgroundPATZ1 fusion-positive central nervous system (CNS) tumors frequently harbor MN1::PATZ1 fusions as driver mutations, provisionally classified as a rare DNA methylation class of low-grade neuroepithelial tumors. Radiographically, they resemble pilocytic astrocytomas with tumor and cystic components, but their supratentorial cortex location and higher recurrence rates are distinguishing features. An intermediate clinical course, despite focal high-grade histopathology, underscores the need for longitudinal molecular and immune analyses to refine classification and standard therapy. Case SummaryA female pediatric patient presented with neurological symptoms, including headache and right upper extremity weakness. MRI revealed a large cystic lesion in the left frontal lobe, leading to a differential diagnosis of low-grade glioma and ependymoma. Genomic analysis identified an MN1::PATZ1 fusion. The tumor recurred after gross total resection prompting a second resection. Transcriptomic and histopathologic assessments identified multiglial lineage, and high-grade features closely related to adult glioblastoma alongside pro-inflammatory activity in the primary tumor. The recurrent tumor showed reduced malignancy, and oligodendroglioma-like features. Increased MHC gene expression, immune checkpoint receptors (PDCD1, CTLA4, TIGIT,TIM3), T cell regulators (CXCR6), and elevated macrophage frequency, coupled with reduced PD-L1 in the recurrent tumor, suggest a complex anti-tumor immune response constrained by T cell dysregulation. This case, along with two other MN1::PATZ1 fusion-positive tumors, identifies a distinct transcriptomic subtype separate from circumscribed astrocytic glioma, highlighting upregulation of growth factor receptor pathways, like PI3K/AKT, and immune dysfunction linked to recurrence. ConclusionLongitudinal multi-omics analyses of recurrent MN1::PATZ1 fusion-positive CNS tumors revealed tumor maturation, immune dysfunction, and potential therapeutic targets. Introductory ParagraphPATZ1 fusion-positive central nervous system (CNS) tumors are rare, predominantly pediatric and frequently recurrent neoplasms provisionally classified as neuroepithelial tumors. Their pronounced histopathological and clinical heterogeneity, along with limited immunological characterization complicates their treatment standardization. We report a new case of an MN1::PATZ1 fusion-positive CNS tumor with recurrence, highlighting its radiographic similarities to low-to-intermediate grade pediatric glioma. Longitudinal multi-omics analyses of this case, along with additional MN1::PATZ1 fusion-positive CNS tumors, however, delineates a transcriptome subtype resembling adult high-grade glioma, with activated oncogenic and pro-inflammatory programs. The recurrent tumor exhibits features of decreased malignancy and enhanced glial differentiation, phenotypically shifting towards oligodendroglioma, suggesting tumor maturation. This was accompanied by increased antigen presentation programs, indicating immune engagement, while increased immune checkpoint expression and microglia/macrophage frequency indicate T cell exhaustion and immunomodulation, respectively. This longitudinal study highlights potential therapeutic strategies targeting both the tumor and its immune environment in MN1::PATZ1 fusion-positive CNS tumors.