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@ARTICLE{Berghoff:178941,
      author       = {A. S. Berghoff and T. Hielscher$^*$ and G. Ricken and J.
                      Furtner and D. Schrimpf$^*$ and G. Widhalm and U. Rajky and
                      C. Marosi and J. A. Hainfellner and A. von Deimling$^*$ and
                      F. Sahm$^*$ and M. Preusser},
      title        = {{P}rognostic impact of genetic alterations and methylation
                      classes in meningioma.},
      journal      = {Brain pathology},
      volume       = {32},
      number       = {2},
      issn         = {1015-6305},
      address      = {Oxford},
      publisher    = {Wiley-Blackwell},
      reportid     = {DKFZ-2022-00357},
      pages        = {e12970},
      year         = {2022},
      note         = {#LA:B300#},
      abstract     = {Meningiomas are classified based on histological features,
                      but genetic and epigenetic features are emerging as relevant
                      biomarkers for outcome prediction and may supplement
                      histomorphological evaluation. We investigated
                      meningioma-relevant mutations and their correlation with DNA
                      methylation clusters and patient survival times.
                      Formalin-fixed and paraffin-embedded samples of 126
                      meningioma patients (WHO grade I 52/126; $41.3\%;$ WHO grade
                      II: 48/126; $38.1\%;$ WHO grade III: 26/126; $20.6\%)$ were
                      investigated. We analyzed NF2, TRAF7, KLF4, ARID, SMO, AKT,
                      TERT promotor, PIK3CA, and SUFU mutations using panel
                      sequencing and correlated them to DNA methylation classes
                      (MC) determined using 850k EPIC arrays. The TRAKL mutation
                      genotype was characterized by the presence of any of the
                      following mutations: TRAF7, AKT1, and KLF4. Survival data
                      including progression-free survival (PFS) and overall
                      survival (OS) was retrieved from chart review. Mutations
                      were evident in 90/126 $(71.4\%)$ specimens with mutations
                      in NF2 (39/126; $31.0\%),$ TRAF7 (39/126; $31.0\%)$ and KLF4
                      (25/126; $19.8\%)$ being the most frequent ones. Two or more
                      mutations were observed in 35/126 $(27.8\%)$ specimens.
                      While TRAKL was predominantly found in benign MC, NF2 was
                      associated with malign MC (p < 0.05). TRAF7, KLF4, and
                      TRAKL mutation genotype were associated with improved PFS
                      and OS (p < 0.05). TERT promotor methylation,
                      intermediate, and malign MC were associated with impaired
                      PFS and OS (p < 0.05). Methylation cluster showed better
                      prognostic discrimination for PFS and OS (c-index 0.77/0.75)
                      than each of the individual mutations (c-index 0.63/0.68).
                      In multivariate analysis correcting for age, gender, MC, and
                      WHO grade, none of the individual mutations except TERT
                      remained an independent significant prognostic factor for
                      PFS. Molecular profiling including mutational analysis and
                      DNA methylation classification may facilitate more precise
                      prognostic assessment and identification of potential
                      targets for personalized therapy in meningioma patients.},
      subtyp        = {Review Article},
      keywords     = {meningioma (Other) / methylation classes (Other) / mutation
                      (Other) / prognosis (Other)},
      cin          = {C060 / B300 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)C060-20160331 / I:(DE-He78)B300-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35213082},
      doi          = {10.1111/bpa.12970},
      url          = {https://inrepo02.dkfz.de/record/178941},
}