PATH-03. FOXR2-OVEREXPRESSING CENTRAL NERVOUS SYSTEM (CNS) TUMORS EXHIBIT SUBSTANTIAL DIVERSITY ACROSS HISTOLOGICAL, MOLECULAR, AND CLINICAL DIMENSIONS

Abstract

Abstract BACKGROUND FOXR2 activation is regarded as the pathognomonic molecular signature of CNS neuroblastoma. However, a comprehensive understanding of the landscape for CNS tumors exhibiting FOXR2 activation is lacking. METHODS Integrated histopathologic, molecular, and clinical data analysis of 36 FOXR2-overexpressing CNS tumors identified through screening of an institutional dataset. RESULTS FOXR2-overexpressing CNS tumors showed a broad anatomic distribution throughout the neuraxis. Of the 36 tumors, 17 (47.2%) were gliomas and 17 (47.2%) were embryonal tumors. The gliomas included 16 high-grade gliomas (eight histone H3 K27M-mutant diffuse midline gliomas, seven radiation-associated tumors, and one with MN1::PATZ1 fusion) and one pilocytic astrocytoma. The embryonal tumors included ten CNS neuroblastomas, six pineoblastomas, and one medulloblastoma. Two were difficult-to-classify high-grade neuroepithelial tumors. The gliomas and embryonal tumors demonstrated comparable FOXR2 expression based on normalized RNA-sequencing data. FOXR2-overexpressing gliomas, but not embryonal tumors, displayed diverse concomitant genetic alterations. The most common mechanisms of FOXR2 activation involved structural alterations leading to proximity effects, frequently incorporating non-canonical non-coding exons, followed by activation of the exon -3 promoter. Tumor location, histology, and concomitant alterations correlated with patient outcomes. While FOXR2-overexpressing gliomas were aggressive with a 5-year overall survival of 13.3%, FOXR2-overexpressing embryonal tumors showed a diverse prognosis. FOXR2-activated CNS neuroblastoma showed a 5-year overall survival of 100%. Pineoblastomas with FOXR2 activation in the PB-FOXR2 DNA methylation group showed a 3-year survival of 0% despite multimodal therapy. The one medulloblastoma patient in the cohort is alive at three years post-diagnosis. CONCLUSION FOXR2-overexpressing CNS tumors manifest significant histological, molecular, and clinical diversity and can occur as post-radiation tumors. Glioma histology and concomitant genetic alterations correlate with treatment resistance and inferior prognosis, while FOXR2-overexpressing embryonal tumors show more heterogeneous outcomes. Integrating histologic and molecular diagnostic approaches along with therapeutic interventions and clinical outcomes is imperative for accurate prognostication and optimal therapeutic decision-making.