HGG-26. Comprehensive Genomic Profiling of Pediatric and AYA High-Grade Gliomas Reveals a High Prevalence of ATRX and Homologous Recombination Repair (HRR) Mutations

Abstract

Abstract BACKGROUND: Pediatric high-grade glioma (HGG) is a devastating heterogenous disease with a clear need for more effective treatment options. Advances in high-throughput molecular sequencing have advanced our understanding of these tumors and yet outcomes remain poor as only a very small subset of patients have demonstrated benefit from targeted therapy approaches. METHODS: We compiled genomic data from 980 pediatric (N=400) and AYA (18 to 30 yrs, N=580) HGG cases that underwent targeted, panel-based comprehensive genomic profiling (FoundationOne® CDx). RESULTS: Among pediatric patients, mutations in ATRX or HRR-related genes were among the most prevalent at 24.25% and 19.5%, respectively. Other commonly occurring mutations were seen in TP53 (58.25%), H3F3A (43%), and PIK3CA/PIK3R1 (22%). Among AYA patients, mutations in ATRX and HRR-related genes were seen in 51.72% and 17.24% of cases, respectively. The most common mutations seen in this older population were in TP53 (76.38%), IDH1/2 (50.86%), PI3KCA/PIK3R1 (20.52%), and H3F3A (18.28%). Among patients with diffuse midline glioma (harboring H3K27M mutations), ATRX and HRR mutations were reported in 21.27% and 13.57% of cases, respectively. Among pediatric patients with histone wild type HGG, mutations in ATRX and HRR-related genes occurred in 20.61% and 21.05% of cases, respectively. CONCLUSION: Alterations in ATRX and HRR-related genes are among the most prevalent mutations in pediatric and AYA HGG. Consideration should be made towards the development of subtype-specific treatment protocols using PARP and/or ATR inhibitors aimed at this subgroup of patients.