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@ARTICLE{Federico:179883,
      author       = {A. Federico$^*$ and C. Thomas and K. Miskiewicz and N.
                      Woltering and F. Zin and K. Nemes and B. Bison and P. D.
                      Johann$^*$ and D. Hawes and S. Bens and U. Kordes and S.
                      Albrecht and H. Dohmen and P. Hauser and K. Keyvani and F.
                      K. H. van Landeghem and E. L. Lund and D. Scheie and C.
                      Mawrin and C.-M. Monoranu and B. Parm Ulhøi and T. Pietsch
                      and H. Reinhard and M. J. Riemenschneider and A. Sehested
                      and D. Sumerauer and R. Siebert and W. Paulus and M. C.
                      Frühwald and M. Kool$^*$ and M. Hasselblatt},
      title        = {{ATRT}-{SHH} comprises three molecular subgroups with
                      characteristic clinical and histopathological features and
                      prognostic significance.},
      journal      = {Acta neuropathologica},
      volume       = {143},
      number       = {6},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2022-00945},
      pages        = {697-711},
      year         = {2022},
      note         = {#EA:B062#LA:B062# / 2022 Jun;143(6):697-711},
      abstract     = {Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive
                      central nervous system tumor characterized by loss of
                      SMARCB1/INI1 protein expression and comprises three distinct
                      molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH
                      represents the largest molecular group and is heterogeneous
                      with regard to age, tumor location and epigenetic profile.
                      We, therefore, aimed to investigate if heterogeneity within
                      ATRT-SHH might also have biological and clinical importance.
                      Consensus clustering of DNA methylation profiles and
                      confirmatory t-SNE analysis of 65 ATRT-SHH yielded three
                      robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2.
                      These subgroups differed by median age of onset (SHH-1A: 18
                      months, SHH-1B: 107 months, SHH-2: 13 months) and tumor
                      location (SHH-1A: $88\%$ supratentorial; SHH-1B: $85\%$
                      supratentorial; SHH-2: $93\%$ infratentorial, often
                      extending to the pineal region). Subgroups showed comparable
                      SMARCB1 mutational profiles, but pathogenic/likely
                      pathogenic SMARCB1 germline variants were over-represented
                      in SHH-2 $(63\%)$ as compared to SHH-1A $(20\%)$ and SHH-1B
                      $(0\%).$ Protein expression of proneural marker ASCL1
                      (enriched in SHH-1B) and glial markers OLIG2 and GFAP
                      (absent in SHH-2) as well as global mRNA expression patterns
                      differed, but all subgroups were characterized by
                      overexpression of SHH as well as Notch pathway members. In a
                      Drosophila model, knockdown of Snr1 (the fly homologue of
                      SMARCB1) in hedgehog activated cells not only altered
                      hedgehog signaling, but also caused aberrant Notch signaling
                      and formation of tumor-like structures. Finally, on survival
                      analysis, molecular subgroup and age of onset (but not ASCL1
                      staining status) were independently associated with overall
                      survival, older patients (> 3 years) harboring SHH-1B
                      experiencing relatively favorable outcome. In conclusion,
                      ATRT-SHH comprises three subgroups characterized by SHH and
                      Notch pathway activation, but divergent molecular and
                      clinical features. Our data suggest that molecular
                      subgrouping of ATRT-SHH has prognostic relevance and might
                      aid to stratify patients within future clinical trials.},
      keywords     = {ASCL1 (Other) / Atypical teratoid/rhabdoid tumor (Other) /
                      DNA methylation profiling (Other) / GFAP (Other) / Gene
                      expression (Other) / Neuroradiology (Other) / OLIG2 (Other)
                      / Overall survival (Other) / Prognosis (Other) / Sonic
                      hedgehog (Other)},
      cin          = {B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / 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:35501487},
      doi          = {10.1007/s00401-022-02424-5},
      url          = {https://inrepo02.dkfz.de/record/179883},
}