Abstract
INTRODUCTION: Mutations in isocitrate dehydrogenase (IDH) enzymes are recognised to drive the molecular footprint of diffuse gliomas through the accumulation of oncometabolite R-2-hydroxyglutarate which drives the widespread restructuring of the DNA methylome; however, beyond R-2-hydroxyglutarate, a comprehensive metabologenomic characterization of IDH-mutant gliomas has yet to be performed. METHODS: Glioma samples from a cohort of 154 patients underwent multiplatform molecular analysis, including metabolomic studies, genome-wide DNA methylation profiling and bulk RNA sequencing. A integrative analysis was performed, including hierarchical clustering and principal component analysis of identified metabolites, differentially methylated probes, copy number alteration and bulk mRNA data. Survival analysis as well as multivariable hazard ratios for clinical variables were calculated by fitting Cox Proportional Hazards Models. RESULTS: We discovered a group of IDH-mutant gliomas whose metabolic profile highly resembled IDH wildtype tumors. Notably, these IDH-mutant gliomas with dysregulated metabolism were distinguished from their IDH-mutant counterparts by significantly shorter overall survival (median OS 118.9 months vs 173.6 months, p=0.048). The IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles. The prognostic relevance of dysregulated metabolism complements, but was not wholly explained by canonically recognized prognostic classifications in IDH-mutant gliomas including 1p/19q codeletion, glioma CpG Island Hypermethylator (GCIMP) status and CDKN2A homozygous deletion. CONCLUSIONS: Utilizing a cross-platform analysis we have uncovered a novel subtyping of IDH-mutant gliomas with dysregulated cellular metabolism with similar survival to IDH-wildtype tumors. The metabolic profile provides unique information on glioma phenotypes, which may facilitate a more comprehensive understanding of glioma biology, and provide a window to target novel dependencies.
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