Integrative Genomics Characterize Medulloblastoma Subtypes

Medulloblastomas, which are highly malignant pediatric brain tumors, have been classified into four molecular subtypes: WNT, SHH, Group 3, and Group 4, the latter three of which are most likely to exhibit a poor clinical outcome. Next-generation sequencing of a large series of tumors revealed the genetics underlying the previously not well understood Group 3 and Group 4 medulloblastomas. To further elucidate the biology of the molecular subtypes of medulloblastoma, Northcott and colleagues performed genomic, epigenomic, and transcriptomic analyses of 491 medulloblastomas. Whole-genome sequencing identified known and previously unidentified medulloblastoma driver genes and pathways which exhibited subtype-specificity. Potential driver events were identified in 76% of Group 3 and 82% of Group 4 medulloblastomas, compared with 32% of Group 3 and 30% of Group 4 medulloblastomas as identified by analysis of previous sequencing data. Integrated epigenomic and transcriptomic analyses of Group 3 and Group 4 medulloblastomas identified 8 methylation subtypes characterized by methylation subtype–specific enrichment of probable driver events. Further, recurrent KBTBD4 mutations were identified in Group 3 and Group 4 medulloblastoma and shown to be the most common candidate driver in two of the methylation subtypes. Integrated analysis of expression, structural variant, topologically associated domains, and enhancer annotation data identified PRDM6 as the most highly significant candidate target of enhancer hijacking in Group 4 medulloblastomas. Together, these results provide a better understanding of the molecular underpinnings of known medulloblastoma subtypes and identify epigenetic subtypes of medulloblastoma, which may aid in the development of targeted therapies.

Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, et al. The whole-genome landscape of medulloblastoma subtypes. Nature 2017;547:311–7.