Tumor mutational burden predicts survival in patients with low-grade gliomas expressing mutated IDH1

Background: Gliomas are the most common primary brain tumors. High-Grade Gliomas have a median survival (MS) of 18 months, while Low-Grade Gliomas (LGGs) have an MS of approximately 7.3 years. Seventy-six percent of patients with LGG express mutated isocitrate dehydrogenase (mIDH) enzyme. Survival of these patients ranges from 1 to 15 years, and tumor mutational burden ranges from 0.28 to 3.85 somatic mutations/megabase per tumor. We tested the hypothesis that the tumor mutational burden would predict the survival of patients with tumors bearing mIDH. Methods: We analyzed the effect of tumor mutational burden on patients' survival using clinical and genomic data of 1199 glioma patients from The Cancer Genome Atlas and validated our results using the Glioma Longitudinal AnalySiS consortium. Results: High tumor mutational burden negatively correlates with the survival of patients with LGG harboring mIDH (P =. 005). This effect was significant for both Oligodendroglioma (LGG-mIDH-O; MS = 2379 vs 4459 days in high vs low, respectively; P =. 005) and Astrocytoma (LGG-mIDH-A; MS = 2286 vs 4412 days in high vs low respectively; P =. 005). There was no differential representation of frequently mutated genes (eg, TP53, ATRX, CIC, and FUBP) in either group. Gene set enrichment analysis revealed an enrichment in Gene Ontologies related to cell cycle, DNA-damage response in high versus low tumor mutational burden. Finally, we identified 6 gene sets that predict survival for LGG-mIDH-A and LGG-mIDH-O. Conclusions: we demonstrate that tumor mutational burden is a powerful, robust, and clinically relevant prognostic factor of MS in mIDH patients.