Medulloblastoma (MB) is the most common malignant brain tumor of childhood and is reported to have a low mutational burden. However, in this study, we identified nine MBs with high mutational burden by next generation sequencing. Of them, two had canonical mutations in the POLE proof-reading domain, where a large proportion of mutations in these tumor genomes contributed to signature 10. We report very rare incidences of hypermutation in MB and mechanisms driving mutagenesis. Strikingly, of the

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... four known molecular subgroups in MB—-SHH, WNT, Group 3, and Group 4—both the POLE-mutated MBs belonged to the SHH subgroup.