Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.

Background: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making.

Materials And Methods: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]).

Results: In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. was most frequently altered (48%; 60/125), and missense (17.6%; 22/125), loss of function (8.8%; 11/125), and (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including , , , , and fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were (49%; 77/157), (37.6%; 59/157), (24.2%; 38/157), (22.2%; 35/157), and (21.7%; 34/157). Interestingly, most mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic , , , and fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in , and genes (78% of cases).

Conclusion: Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy.

Implications For Practice: By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors.