Identification of the Prognostic Signatures for Isocitrate Dehydrogenase Mutant Glioma

Abstract

Diffuse gliomas can be divided based on presence or absence of mutation in isocitrate dehydrogenase (IDH) genes. IDH-mutant diffuse gliomas represent a wide range of clinical outcome, which is not accounted for by current clinical and pathologic parameters. To address this, we aim to identify and characterize a predictive signature of outcome in diffuse gliomas to better understand this heterogeneity in outcome. A total of 310 IDH mutant glioma samples with methylation data were used for the analysis together with 419 samples from The Cancer Genome Atlas (TCGA), utilizing methylation, mRNA, copy number variation (CNV) and mutation data to identify unique molecular signatures that predict patient outcome. Methylation analysis from our test cohort identified signatures from Cox regression analysis that split the glioma cohort into two prognostic groups that strongly predicted survival (p-value < 0.0001). The CpG-based signatures were reliably validated using two independent validation datasets from TCGA and DKFZ (German Cancer Research Center) cohorts (both p-values < 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. These results demonstrate the importance of HOX genes in the outcome of diffuse gliomas to identify relevant molecular subtyping indistinguishable under the microscope within a histology.