Our prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas within the cerebral hemispheres of adults identified a distinct subgroup defined by the combination of somatic hypermutation (TMB of ≥ 15 somatic mutations per Mb) and biallelic inactivation of a canonical mismatch repair gene (MSH2, MSH6, MLH1, or PMS2) with loss of the affected mismatch repair protein by immunohistochemistry (Table 1, Supplementary Tables S1 and S2). Here, MLH1 is linked to glioblastoma.