Collectively, our data provide a conceptual framework to explore the molecular drivers of genetic alterations and epigenetic plasticity contributing to G-CIMP malignant evolution toward an IDH-wild-type and mesenchymal/stem cell-like glioblastoma phenotype, a platform for identifying tumors and patients that best respond to certain therapies, and predictive biomarkers for refining clinical trial designs to determine optimal management of patients at risk for malignant glioma recurrences. Here, IDH1 is linked to malignant glioma.