This loss may occur via biallelic mutation, epigenetic silencing via CpG island methylation, loss of heterozygosity, or a combination of these mechanisms.46 Numerous previous studies have demonstrated that MMR mutations may also arise spontaneously or in response to alkylating therapy in existing IDH-mutant astrocytomas and IDH-wild-type glioblastomas,14–16 or may be present prior to tumor formation, particularly in cases with germline MMR mutation. This evidence concerns the gene IDH1 and glioblastoma.