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@ARTICLE{Capper:136668,
      author       = {D. Capper$^*$ and N. W. Engel and D. Stichel$^*$ and M.
                      Lechner and S. Glöss$^*$ and S. Schmid$^*$ and C.
                      Koelsche$^*$ and D. Schrimpf$^*$ and J. Niesen and A. K.
                      Wefers$^*$ and D. Jones$^*$ and M. Sill$^*$ and O. Weigert
                      and K. L. Ligon and A. Olar and A. Koch and M. Forster and
                      S. Moran and O. M. Tirado and M. Sáinz-Jaspeado and J. Mora
                      and M. Esteller and J. Alonso and X. G. Del Muro and W.
                      Paulus and J. Felsberg$^*$ and G. Reifenberger$^*$ and M.
                      Glatzel and S. Frank and C. M. Monoranu and V. J. Lund and
                      A. von Deimling$^*$ and S. Pfister$^*$ and R. Buslei and J.
                      Ribbat-Idel and S. Perner and V. Gudziol and M. Meinhardt
                      and U. Schüller},
      title        = {{DNA} methylation-based reclassification of olfactory
                      neuroblastoma.},
      journal      = {Acta neuropathologica},
      volume       = {136},
      number       = {2},
      issn         = {1432-0533},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2018-01137},
      pages        = {255 - 271},
      year         = {2018},
      abstract     = {Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an
                      uncommon neuroectodermal neoplasm thought to arise from the
                      olfactory epithelium. Little is known about its molecular
                      pathogenesis. For this study, a retrospective cohort of
                      n = 66 tumor samples with the institutional diagnosis of
                      ONB was analyzed by immunohistochemistry, genome-wide DNA
                      methylation profiling, copy number analysis, and in a
                      subset, next-generation panel sequencing of 560
                      tumor-associated genes. DNA methylation profiles were
                      compared to those of relevant differential diagnoses of ONB.
                      Unsupervised hierarchical clustering analysis of DNA
                      methylation data revealed four subgroups among
                      institutionally diagnosed ONB. The largest group
                      (n = 42, $64\%,$ Core ONB) presented with classical ONB
                      histology and no overlap with other classes upon methylation
                      profiling-based t-distributed stochastic neighbor embedding
                      (t-SNE) analysis. A second DNA methylation group (n = 7,
                      $11\%)$ with CpG island methylator phenotype (CIMP)
                      consisted of cases with strong expression of cytokeratin, no
                      or scarce chromogranin A expression and IDH2 hotspot
                      mutation in all cases. T-SNE analysis clustered these cases
                      together with sinonasal carcinoma with IDH2 mutation. Four
                      cases $(6\%)$ formed a small group characterized by an
                      overall high level of DNA methylation, but without CIMP. The
                      fourth group consisted of 13 cases that had heterogeneous
                      DNA methylation profiles and strong cytokeratin expression
                      in most cases. In t-SNE analysis, these cases mostly grouped
                      among sinonasal adenocarcinoma, squamous cell carcinoma, and
                      undifferentiated carcinoma. Copy number analysis indicated
                      highly recurrent chromosomal changes among Core ONB with a
                      high frequency of combined loss of chromosome 1-4, 8-10, and
                      12. NGS sequencing did not reveal highly recurrent mutations
                      in ONB, with the only recurrently mutated genes being TP53
                      and DNMT3A. In conclusion, we demonstrate that
                      institutionally diagnosed ONB are a heterogeneous group of
                      tumors. Expression of cytokeratin, chromogranin A, the
                      mutational status of IDH2 as well as DNA methylation
                      patterns may greatly aid in the precise classification of
                      ONB.},
      cin          = {G380 / L101 / B062 / L201 / L401},
      ddc          = {610},
      cid          = {I:(DE-He78)G380-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)L201-20160331 /
                      I:(DE-He78)L401-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29730775},
      doi          = {10.1007/s00401-018-1854-7},
      url          = {https://inrepo02.dkfz.de/record/136668},
}