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@ARTICLE{Lindsey:127019,
      author       = {J. C. Lindsey and D. Kawauchi$^*$ and E. C. Schwalbe and D.
                      J. Solecki and M. P. Selby and P. J. McKinnon and J. M.
                      Olson and J. T. Hayden and R. G. Grundy and D. W. Ellison
                      and D. Williamson and S. Bailey and M. F. Roussel and S. C.
                      Clifford},
      title        = {{C}ross-species epigenetics identifies a critical role for
                      {VAV}1 in {SHH} subgroup medulloblastoma maintenance.},
      journal      = {Oncogene},
      volume       = {34},
      number       = {36},
      issn         = {1476-5594},
      address      = {Basingstoke},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2017-03045},
      pages        = {4746 - 4757},
      year         = {2015},
      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.},
      keywords     = {Proto-Oncogene Proteins c-vav (NLM Chemicals) / VAV1
                      protein, human (NLM Chemicals)},
      cin          = {B062},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25531316},
      pmc          = {pmc:PMC4386991},
      doi          = {10.1038/onc.2014.405},
      url          = {https://inrepo02.dkfz.de/record/127019},
}