Together, these findings indicate that de novo RRD glioblastomas have a unique hypomethylated epigenetic signature compared to established adult IDH-wildtype glioblastoma reference classes, with closest similarity to a novel subclass of diffuse pediatric-type high-grade gliomas that includes those arising in the setting of CMMRD, but may be epigenetically heterogeneous. Here, IDH1 is linked to central nervous system cancer.