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

Lookup NU author(s): Dr Janet Lindsey, Dr Ed Schwalbe, Matthew Selby, Dr James Hayden, Dr Daniel Williamson, Professor Simon Bailey, Professor Steven Clifford

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Abstract

The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) 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 MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 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 hypomethylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH 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 germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.


Publication metadata

Author(s): Lindsey JC, Kawauchi D, Schwalbe EC, Solecki DJ, Selby MP, McKinnon PJ, Olson JM, Hayden JT, Grundy RG, Ellison DW, Williamson D, Bailey S, Roussel MF, Clifford SC

Publication type: Article

Publication status: Published

Journal: Oncogene

Year: 2015

Volume: 34

Issue: 36

Pages: 4746-4757

Print publication date: 01/01/2015

Online publication date: 22/12/2014

Acceptance date: 03/11/2014

ISSN (print): 0950-9232

ISSN (electronic): 1476-5594

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/onc.2014.405

DOI: 10.1038/onc.2014.405


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