POLE and glioblastoma: While the mutational signature of the other six de novo RRD glioblastomas was predominantly composed of C > T:G > A transitions and small indel mutations consistent with mutagenesis caused by underlying mismatch repair deficiency, the mutational signature in the three ultrahypermutated de novo RRD glioblastomas with accompanying POLE mutations featured a major component of C > A:G > T transversions occurring at cytosines with flanking thymine bases consistent with mutagenesis caused by underlying DNA polymerase proofreading deficiency (Supplementary Table S3) [1, 12, 43].