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@ARTICLE{Dodgshun:163689,
      author       = {A. J. Dodgshun and K. Fukuoka and M. Edwards and V. J.
                      Bianchi and A. Das and A. Sexton-Oates and V. Larouche and
                      M. I. Vanan and S. Lindhorst and M. Yalon and G. Mason and
                      B. Crooks and S. Constantini and M. Massimino and S.
                      Chiaravalli and J. Ramdas and W. Mason and S. Ashraf and R.
                      Farah and A. Van Damme and E. Opocher and S. A. Hamid and D.
                      S. Ziegler and D. Samuel and K. A. Cole and P. Tomboc and D.
                      Stearns and G. A. Thomas and A. Lossos and M. Sullivan and
                      J. R. Hansford and A. Mackay and C. Jones and D. T. W.
                      Jones$^*$ and V. Ramaswamy and C. Hawkins and E. Bouffet and
                      U. Tabori},
      title        = {{G}ermline-driven replication repair-deficient high-grade
                      gliomas exhibit unique hypomethylation patterns.},
      journal      = {Acta neuropathologica},
      volume       = {140},
      number       = {5},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2020-01965},
      pages        = {765-776},
      year         = {2020},
      note         = {2020 Nov;140(5):765-776},
      abstract     = {Replication repair deficiency (RRD) leading to
                      hypermutation is an important driving mechanism of
                      high-grade glioma (HGG) occurring predominantly in the
                      context of germline mutations in RRD-associated genes.
                      Although HGG presents specific patterns of DNA methylation
                      corresponding to oncogenic mutations, this has not been well
                      studied in replication repair-deficient tumors. We analyzed
                      51 HGG arising in the background of gene mutations in RRD
                      utilizing either 450 k or 850 k methylation arrays. These
                      were compared with HGG not known to be from patients with
                      RRD. RRD HGG harboring secondary mutations in glioma genes
                      such as IDH1 and H3F3A displayed a methylation pattern
                      corresponding to these methylation subgroups. Strikingly,
                      RRD HGG lacking these known secondary mutations clustered
                      together with an incompletely described group of HGG
                      previously labeled 'Wild type-C' or 'Paediatric RTK 1'.
                      Independent analysis of two comparator HGG cohorts showed
                      that other RRD/hypermutant tumors clustered within these
                      subgroups, suggesting that undiagnosed RRD may be driving
                      some HGG clustering in this location. RRD HGG displayed a
                      unique CpG Island Demethylator Phenotype in contrast to the
                      CpG Island Methylator Phenotype described in other cancers.
                      Hypomethylation was enriched at gene promoters with
                      prominent demethylation in genes and pathways critical to
                      cellular survival including cell cycle, gene expression,
                      cellular metabolism, and organization. These data suggest
                      that methylation arrays may provide diagnostic information
                      for the detection of RRD HGG. Furthermore, our findings
                      highlight the unique natural selection pressures in these
                      highly dysregulated, hypermutant cancers and provide the
                      novel impact of hypermutation and RRD on the cancer
                      epigenome.},
      cin          = {B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B360-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32895736},
      doi          = {10.1007/s00401-020-02209-8},
      url          = {https://inrepo02.dkfz.de/record/163689},
}