title: Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance.
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 hypo-methylation 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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level 5, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Lindsey
authors.affiliation: Department of Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kawauchi
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level 5, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: E C
authors.initials: EC
authors.lastname: Schwalbe
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Solecki
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level 5, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: M P
authors.initials: MP
authors.lastname: Selby
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: McKinnon
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Olson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level 5, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: Hayden
authors.affiliation: Children's Brain Tumor Research Centre, University of Nottingham, Nottingham, UK.
authors.forename: R G
authors.initials: RG
authors.lastname: Grundy
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level 5, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: D
authors.initials: D
authors.lastname: Williamson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level 5, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: S
authors.initials: S
authors.lastname: Bailey
authors.affiliation: Department of Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Roussel
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level 5, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: S C
authors.initials: SC
authors.lastname: Clifford
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051567:Proto-Oncogene Proteins c-vav / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human