Tumor Mutation Burden and Driver Mutations: Further Insight into the Genomic Landscape of Pediatric Brain Tumors

Abstract

To investigate the relationship between tumor mutation burden (TMB) and driver mutations and their role as predictive biomarkers to guide targeted therapy in pediatric brain tumors. Higher TMB has been found to relate to lower incidence of driver mutations, but this relationship has not been studied in pediatric brain tumors. To characterize the association between TMB and known driver mutations, comprehensive genomic profiling (CGP) was performed on 723 pediatric (≤21 years) brain tumor samples using DNA extracted from 40 microns of formalin-fixed paraffin-embedded tissue. CGP utilized hybridization-captured, adaptor ligation-based libraries sequenced to a mean coverage depth of >500X for up to 315 cancer-related genes. TMB was calculated as mutations per megabase and categorized as low (0-6), intermediate (6-20), or high (20+). Analysis included 80 clinically relevant driver mutations; genomic alterations known to confer a selective growth advantage. Of 723 brain tumors, TMB was low in 91.8%, intermediate in 6.1%, and high in 2.1%. When excluding tumor suppressor genes (TSGs), there was a decreased incidence of driver mutations in high TMB tumors (p<0.001). Additionally, BRAF alterations were not identified in high TMB tumors, but were enriched in low TMB tumors (p<0.01). H3F3A alterations were associated with a higher TMB despite not having any incidence in high TMB tumors; they were enriched in intermediate TMB tumors. When including TSGs, however, 93% of tumors in the high TMB cohort harbored a driver mutation; 70% and 63% in the intermediate and low TMB cohorts, respectively (p<0.05). There is an association between high TMB and incidence of TSG alterations (p<10-10), especially TP53 alterations (p<10-13). Of the 15 tumors with high TMB, 14 were high grade gliomas (HGG) and had alterations in TP53; the one high TMB tumor that was not a HGG also did not have a TP53 mutation. Three biallelic mismatch repair mutations identified were MSH2, MSH6, and PMS2; they were associated with a higher TMB (p<0.01). This is the first study to compare TMB with incidence of driver mutations in pediatric brain tumors and demonstrates that the relationship may depend on the type of driver mutation present. Patients with high TMB have the potential to respond to immunotherapy, with long-term sustained remission as TMB is associated with a higher level of neoantigens and an increased immunogenicity. Future studies should focus on identifying optimal treatment strategies for these subsets of patients, including using immunotherapy with radiotherapy, as preclinical data suggests the combination may be more effective. Characterizing pediatric brain tumors by TMB and driver mutations may represent a rapid method of risk stratification and potentially predict clinical response to immunotherapy with or without adjuvant radiation and chemotherapy.