These results provide insights into the tumorigenic events that contribute to G-CIMP progression, with opportunity for further targeted therapy exploitation as well as a inclusion in clinical trials design to impede or prevent tumor malignant transformation and progression to G-CIMP-low, an IDH-wild-type GBM-like tumor phenotype associated with IDH mutant non-Codel gliomas. Here, IDH2 is linked to glioma.