PATH-04. Defining PATZ1-Fused CNS Tumors as a Distinct Entity: Insights from Methylation Landscapes, Clinicopathological Correlation, and Comparative Survival with Peripheral Counterparts

Abstract OBJECTIVE To investigate the clinicopathological and molecular characteristics, prognosis, and biological significance of central nervous system (CNS) tumors with PATZ1 fusions as distinct entities by comparing them with peripheral soft tissue sarcomas. METHODS Five CNS PATZ1-fused tumors and one peripheral sarcoma were analyzed through histomorphological evaluation, immunohistochemistry (IHC), DNA methylation profiling, RNA sequencing, and survival analysis. A comprehensive literature review of 127 reported cases (80 CNS, 47 peripheral) was conducted to compare clinicopathological and molecular features. RESULTS CNS cases predominantly affected younger patients (median age: 11.5 vs. 47.5 years in peripheral cases; P<0.001), with supratentorial localization (frontal lobe: 44%, parietal lobe: 36%). Two histopathological patterns were identified: (1) neuroepithelial-like morphology (GFAP/Olig2-positive, absent reticular fibers) and (2) sarcomatoid morphology (glial marker-negative, abundant reticular fibers). Molecular profiling revealed EWSR1:PATZ1 (56%) and MN1:PATZ1 (25%) as major fusion types. Methylation analysis classified most CNS tumors under the “HGNET PATZ1 fusion-positive” cluster, while a novel LOC10192943-PATZ1 fusion case overlapped with astroblastoma. Survival outcomes for CNS cases were superior to peripheral sarcomas (median OS: 31 vs. 14 months, P=0.0035; median PFS: 25 vs. 10.5 months, P=0.0084). CONCLUSION CNS PATZ1-fused tumors exhibit distinct clinicopathological and molecular profiles, with DNA methylation profiling aiding accurate classification. Significant heterogeneity exists, including molecular overlap with astroblastoma, necessitating integrated multi-omics diagnostics. Sarcomatoid subtypes may require tailored therapeutic strategies. This study underscores the importance of recognizing PATZ1-fused CNS tumors as unique entities, providing critical insights for classification, prognostication, and personalized treatment.