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@ARTICLE{Olar:120434,
      author       = {A. Olar and K. M. Wani and C. D. Wilson and G. Zadeh and F.
                      DeMonte and D. Jones$^*$ and S. Pfister$^*$ and E. P. Sulman
                      and K. D. Aldape},
      title        = {{G}lobal epigenetic profiling identifies methylation
                      subgroups associated with recurrence-free survival in
                      meningioma.},
      journal      = {Acta neuropathologica},
      volume       = {133},
      number       = {3},
      issn         = {1432-0533},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2017-00863},
      pages        = {431 - 444},
      year         = {2017},
      abstract     = {Meningioma is the most common primary brain tumor and
                      carries a substantial risk of local recurrence. Methylation
                      profiles of meningioma and their clinical implications are
                      not well understood. We hypothesized that aggressive
                      meningiomas have unique DNA methylation patterns that could
                      be used to better stratify patient management. Samples
                      (n = 140) were profiled using the Illumina
                      HumanMethylation450BeadChip. Unsupervised modeling on a
                      training set (n = 89) identified 2 molecular methylation
                      subgroups of meningioma (MM) with significantly different
                      recurrence-free survival (RFS) times between the groups: a
                      prognostically unfavorable subgroup (MM-UNFAV) and a
                      prognostically favorable subgroup (MM-FAV). This finding was
                      validated in the remaining 51 samples and led to a baseline
                      meningioma methylation classifier (bMMC) defined by 283 CpG
                      loci (283-bMMC). To further optimize a recurrence predictor,
                      probes subsumed within the baseline classifier were subject
                      to additional modeling using a similar training/validation
                      approach, leading to a 64-CpG loci meningioma methylation
                      predictor (64-MMP). After adjustment for relevant clinical
                      variables [WHO grade, mitotic index, Simpson grade, sex,
                      location, and copy number aberrations (CNAs)] multivariable
                      analyses for RFS showed that the baseline methylation
                      classifier was not significant (p = 0.0793). The
                      methylation predictor, however, was significantly associated
                      with tumor recurrence (p < 0.0001). CNAs were extracted
                      from the 450k intensity profiles. Tumor samples in the
                      MM-UNFAV subgroup showed an overall higher proportion of
                      CNAs compared to the MM-FAV subgroup tumors and the CNAs
                      were complex in nature. CNAs in the MM-UNFAV subgroup
                      included recurrent losses of 1p, 6q, 14q and 18q, and gain
                      of 1q, all of which were previously identified as indicators
                      of poor outcome. In conclusion, our analyses demonstrate
                      robust DNA methylation signatures in meningioma that
                      correlate with CNAs and stratify patients by recurrence
                      risk.},
      cin          = {B062 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)L101-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28130639},
      doi          = {10.1007/s00401-017-1678-x},
      url          = {https://inrepo02.dkfz.de/record/120434},
}