PATH-08. A COMPREHENSIVE GENOMIC STUDY OF 390 H3F3A-MUTANT PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMAS WHO CNS GRADE 4

Abstract OBJECTIVES Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and hemispheric (DHG) H3G34-mutant occur in all age groups can have significant variation clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections H3F3A-mutant analyzed to date, identifying subsets defined by recurrently co-mutated genes. METHODS We identified 390 WHO grade 4 (201 females 189 males) that were profiled program at Foundation Medicine between 2013-2020. Information pathology reports, histopathology reviews, data was assessed. RESULTS Our cohort comprised 304 (77.9%) H3K27M-mutant DMG (156 148 86 DHG (45 41 with a median 20 years (1-74 years). distributed equally pediatric adult patients, 52% patients older than years, 30% 30 18% 40 time first diagnosis. Clonal FGFR1 hotspot mutations exclusively detected K27M-mutant (n = 64/304, 21%; p=0.0001), association higher diagnosis (median 32.5 years), wide tumor distribution across diencephalon. Additional genes which significantly more frequently altered compared G34-mutant included NF1 (31% vs. 8.1%; p=0.0001) PIK3CA/PIK3R1 (27.9% 15.1%; p=0.016). Conversely, targetable alterations cell-cycle pathway (CDK4/6 amplifications CDKN2A/B deletions) enriched (26%) (7%). Potentially PDGFR present 32.5% DMG. CONCLUSIONS These expand our understanding tumor-specific molecular features pediatric-type high-grade gliomas, sub-structure recurrent co-mutations, inform trial design.