Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance

The identification of key tumorigenic events in Sonic Hedgehog subgroup medulloblastomas (MB(SHH)) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH-pathway mutations, recent genome-wide sequencing studies have not revealed commonly-mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MB(SHH) using a cross-species approach to candidate identification, prioritization and validation. MB(SHH)–associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MB(SHH), 28 WNT(,) 44 Group 3, 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event which characterizes the majority of MB(SHH) tumors in both species, and is associated with a poor outcome in MB(SHH) patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor (GNP) germinal zone exit and migration initiation in an ex vivo model of early post-natal cerebellar development. These findings establish VAV1 as a critical epigenetically-regulated oncogene with a key role in MB(SHH) maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.