000127019 001__ 127019
000127019 005__ 20240228140901.0
000127019 0247_ $$2doi$$a10.1038/onc.2014.405
000127019 0247_ $$2pmid$$apmid:25531316
000127019 0247_ $$2pmc$$apmc:PMC4386991
000127019 0247_ $$2ISSN$$a0950-9232
000127019 0247_ $$2ISSN$$a1476-5594
000127019 0247_ $$2altmetric$$aaltmetric:3009370
000127019 037__ $$aDKFZ-2017-03045
000127019 041__ $$aeng
000127019 082__ $$a610
000127019 1001_ $$aLindsey, J. C.$$b0
000127019 245__ $$aCross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance.
000127019 260__ $$aBasingstoke$$bNature Publ. Group$$c2015
000127019 3367_ $$2DRIVER$$aarticle
000127019 3367_ $$2DataCite$$aOutput Types/Journal article
000127019 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1508835331_20352
000127019 3367_ $$2BibTeX$$aARTICLE
000127019 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000127019 3367_ $$00$$2EndNote$$aJournal Article
000127019 520__ $$aThe identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.
000127019 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
000127019 588__ $$aDataset connected to CrossRef, PubMed,
000127019 650_7 $$2NLM Chemicals$$aProto-Oncogene Proteins c-vav
000127019 650_7 $$2NLM Chemicals$$aVAV1 protein, human
000127019 7001_ $$0P:(DE-He78)0ac2bd1a9fb1823a351ee4434d80808b$$aKawauchi, D.$$b1$$udkfz
000127019 7001_ $$aSchwalbe, E. C.$$b2
000127019 7001_ $$aSolecki, D. J.$$b3
000127019 7001_ $$aSelby, M. P.$$b4
000127019 7001_ $$aMcKinnon, P. J.$$b5
000127019 7001_ $$aOlson, J. M.$$b6
000127019 7001_ $$aHayden, J. T.$$b7
000127019 7001_ $$aGrundy, R. G.$$b8
000127019 7001_ $$aEllison, D. W.$$b9
000127019 7001_ $$aWilliamson, D.$$b10
000127019 7001_ $$aBailey, S.$$b11
000127019 7001_ $$aRoussel, M. F.$$b12
000127019 7001_ $$aClifford, S. C.$$b13
000127019 773__ $$0PERI:(DE-600)2008404-3$$a10.1038/onc.2014.405$$gVol. 34, no. 36, p. 4746 - 4757$$n36$$p4746 - 4757$$tOncogene$$v34$$x1476-5594$$y2015
000127019 909CO $$ooai:inrepo02.dkfz.de:127019$$pVDB
000127019 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)0ac2bd1a9fb1823a351ee4434d80808b$$aDeutsches Krebsforschungszentrum$$b1$$kDKFZ
000127019 9131_ $$0G:(DE-HGF)POF3-312$$1G:(DE-HGF)POF3-310$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lKrebsforschung$$vFunctional and structural genomics$$x0
000127019 9141_ $$y2015
000127019 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bONCOGENE : 2015
000127019 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS
000127019 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline
000127019 915__ $$0StatID:(DE-HGF)0310$$2StatID$$aDBCoverage$$bNCBI Molecular Biology Database
000127019 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search
000127019 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC
000127019 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bThomson Reuters Master Journal List
000127019 915__ $$0StatID:(DE-HGF)0110$$2StatID$$aWoS$$bScience Citation Index
000127019 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection
000127019 915__ $$0StatID:(DE-HGF)0111$$2StatID$$aWoS$$bScience Citation Index Expanded
000127019 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences
000127019 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews
000127019 915__ $$0StatID:(DE-HGF)9905$$2StatID$$aIF >= 5$$bONCOGENE : 2015
000127019 9201_ $$0I:(DE-He78)B062-20160331$$kB062$$lPädiatrische Neuroonkologie$$x0
000127019 980__ $$ajournal
000127019 980__ $$aVDB
000127019 980__ $$aI:(DE-He78)B062-20160331
000127019 980__ $$aUNRESTRICTED