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@ARTICLE{Kessler:132534,
      author       = {T. Kessler$^*$ and F. Sahm$^*$ and A. Sadik$^*$ and D.
                      Stichel$^*$ and A. Hertenstein$^*$ and G. Reifenberger and
                      A. Zacher and M. Sabel and G. Tabatabai$^*$ and J.
                      Steinbach$^*$ and U. Sure$^*$ and D. Krex$^*$ and A.-L.
                      Grosu$^*$ and M. Bewerunge-Hudler$^*$ and D. Jones$^*$ and
                      S. Pfister$^*$ and M. Weller and C. Opitz$^*$ and M.
                      Bendszus and A. von Deimling$^*$ and M. Platten$^*$ and W.
                      Wick$^*$},
      title        = {{M}olecular differences in {IDH} wildtype glioblastoma
                      according to {MGMT} promoter methylation.},
      journal      = {Neuro-Oncology},
      volume       = {20},
      number       = {3},
      issn         = {1523-5866},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2018-00218},
      pages        = {367 - 379},
      year         = {2018},
      abstract     = {O6-methylguanine-DNA-methyltransferase (MGMT) promoter
                      methylation status is a predictive biomarker in
                      glioblastoma. We investigated whether this marker
                      furthermore defines a molecularly distinct tumor subtype
                      with clinically different outcome.We analyzed copy number
                      variation (CNV) and methylation profiles of 1095 primary and
                      92 progressive isocitrate dehydrogenase wildtype
                      glioblastomas, including paired samples from 49 patients.
                      DNA mutation data from 182 glioblastoma samples of The
                      Cancer Genome Atlas (TCGA) and RNA expression from 107 TCGA
                      and 55 Chinese Glioma Genome Atlas samples were
                      analyzed.Among untreated glioblastomas, MGMT promoter
                      methylated (mMGMT) and unmethylated (uMGMT) tumors did not
                      show different CNV or specific gene mutations, but a higher
                      mutation count in mMGMT tumors. We identified 3 methylation
                      clusters. Cluster 1 showed the highest average methylation
                      and was enriched for mMGMT tumors. Seventeen genes including
                      gastrulation brain homeobox 2 (GBX2) were found to be
                      hypermethylated and downregulated on the mRNA level in mMGMT
                      tumors. In progressive glioblastomas, platelet derived
                      growth factor receptor alpha (PDGFRA) and GLI2
                      amplifications were enriched in mMGMT tumors. Methylated
                      MGMT tumors gain PDGFRA amplification of PDGFRA, whereas
                      uMGMT tumors with amplified PDGFRA frequently lose this
                      amplification upon progression. Glioblastoma patients
                      surviving <6 months and with mMGMT harbored less frequent
                      epidermal growth factor receptor (EGFR) amplifications, more
                      frequent TP53 mutations, and a higher tumor necrosis
                      factor-nuclear factor-kappaB (TNF-NFκB) pathway activation
                      compared with patients surviving >12 months.MGMT promoter
                      methylation status does not define a molecularly distinct
                      glioblastoma subpopulation among untreated tumors.
                      Progressive mMGMT glioblastomas and mMGMT tumors of patients
                      with short survival tend to have more unfavorable molecular
                      profiles.},
      cin          = {G370 / L101 / G380 / G161 / L801 / L601 / W110 / G160 /
                      B062},
      ddc          = {610},
      cid          = {I:(DE-He78)G370-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)G380-20160331 / I:(DE-He78)G161-20160331 /
                      I:(DE-He78)L801-20160331 / I:(DE-He78)L601-20160331 /
                      I:(DE-He78)W110-20160331 / I:(DE-He78)G160-20160331 /
                      I:(DE-He78)B062-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29016808},
      pmc          = {pmc:PMC5817966},
      doi          = {10.1093/neuonc/nox160},
      url          = {https://inrepo02.dkfz.de/record/132534},
}