Mutations in different epigenetic modifiers may distinguish medulloblastoma subgroups.

  • Major finding: Mutations in different epigenetic modifiers may distinguish medulloblastoma subgroups.

  • Concept: Mutations in H3K27me3 modifiers and β-catenin interactors are subgroup specific.

  • Impact: Drugs targeting subgroup-specific alterations may be more effective and less toxic.

Based primarily on gene expression profiles, medulloblastomas can be classified into 4 different subgroups—sonic hedgehog, WNT, subgroup 3, and subgroup 4—that differ in cell of origin, karyotype, histology, and prognosis. However, all the subgroups are treated with the same combination of surgery, radiation, and chemotherapy, which fails in up to half of children with aggressive disease and leads to long-term deficits in survivors. To identify recurrent somatic alterations that may lead to more effective and less toxic subgroup-specific therapies, Robinson and colleagues performed whole-genome sequencing on 37 medulloblastomas representing all 4 subgroups and sequenced recurrently mutated genes in a validation cohort of 56 additional tumors. Interestingly, subgroup-3 and -4 tumors were significantly enriched for mutations that cause aberrant accumulation of histone H3 lysine 27 trimethylation (H3K27me3). EZH2, encoding an H3K27me3 methyltransferase, was specifically gained and overexpressed in these tumors, and the samples with lower EZH2 expression tended to have inactivating mutations of lysine (K)-specific demethylase (KDM) family H3K27me3 demethylases. Given that human subgroup-3 and -4 tumors had significantly higher levels of H3K27me3 than those in the WNT- and SHH-subgroup tumors, these findings suggest that gain of EZH2 and loss of KDM genes create a unique epigenetic landscape in these tumors. Unlike subgroup-3 and -4 tumors, WNT-subgroup tumors selectively harbored mutations in genes encoding proteins that are recruited by β-catenin to remodel chromatin and regulate transcription at WNT-responsive genes, including SMARCA4 (a subunit of the SWI/SNF nucleosome remodeling complex); CREBBP and TRAAP (histone acetyltransferases); and MED13 (a subunit of the mediator complex). Together, these findings provide insight into the underlying biology of the different medulloblastoma subgroups and suggest that EZH2 inhibitors may be effective in subgroup-3 and -4 disease.

Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 2012 Jun 20 [Epub ahead of print].

©2012 American Association for Cancer Research.
2012