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@ARTICLE{Richardson:169868,
      author       = {S. Richardson and R. M. Hill and C. Kui and J. C. Lindsey
                      and Y. Grabovksa and C. Keeling and L. Pease and M. Bashton
                      and S. Crosier and M. Vinci and N. André and D.
                      Figarella-Branger and J. R. Hansford and M. Lastowska and K.
                      Zakrzewski and M. Jorgensen and J. C. Pickles and M. D.
                      Taylor and S. M. Pfister$^*$ and S. B. Wharton and B. Pizer
                      and A. Michalski and A. Joshi and T. S. Jacques and D. Hicks
                      and E. C. Schwalbe and D. Williamson and V. Ramaswamy and S.
                      Bailey and S. C. Clifford},
      title        = {{E}mergence and maintenance of actionable genetic drivers
                      at medulloblastoma relapse.},
      journal      = {Neuro-Oncology},
      volume       = {24},
      number       = {1},
      issn         = {1523-5866},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2021-01602},
      pages        = {153-165},
      year         = {2022},
      note         = {2022 Jan 5;24(1):153-165},
      abstract     = {$<5\%$ of medulloblastoma patients survive following
                      failure of contemporary radiation-based therapies.
                      Understanding the molecular drivers of medulloblastoma
                      relapse (rMB) will be essential to improve outcomes. Initial
                      genome-wide investigations suggested significant genetic
                      divergence of the relapsed disease.We undertook large-scale
                      integrated characterization of the molecular features of rMB
                      - molecular subgroup, novel subtypes, copy number variation
                      (CNV) and driver gene mutation. 119 rMBs were assessed in
                      comparison with their paired diagnostic samples (n=107),
                      alongside an independent reference cohort sampled at
                      diagnosis (n=282). rMB events were investigated for
                      association with outcome post-relapse in
                      clinically-annotated patients (n=54).Significant genetic
                      evolution occurred over disease-course; $40\%$ of putative
                      rMB drivers emerged at relapse and differed significantly
                      between molecular subgroups. MBSHH Non-infant displayed
                      significantly more chromosomal CNVs at relapse (TP53
                      mutation-associated). Relapsed MBGroup4 demonstrated the
                      greatest genetic divergence, enriched for targetable (e.g.
                      CDK amplifications) and novel (e.g. USH2A mutations) events.
                      Importantly, many hallmark features of medulloblastoma were
                      stable over time; novel subtypes $(>90\%$ of tumors) and
                      established genetic drivers (e.g. SHH/WNT/P53 mutations;
                      $60\%$ of rMB events) were maintained from diagnosis.
                      Critically, acquired and maintained rMB events converged on
                      targetable pathways which were significantly enriched at
                      relapse (e.g. DNA damage-signaling) and specific events
                      (e.g. 3p loss) predicted survival post-relapse.rMB is
                      defined by the emergence of novel events and pathways, in
                      concert with selective maintenance of established genetic
                      drivers. Together, these define the actionable genetic
                      landscape of rMB and provide a basis for improved clinical
                      management and development of stratified therapeutics,
                      across disease-course.},
      keywords     = {Drivers (Other) / Genomics (Other) / Medulloblastoma
                      (Other) / Relapse (Other) / Subgroups (Other)},
      cin          = {B062},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34272868},
      doi          = {10.1093/neuonc/noab178},
      url          = {https://inrepo02.dkfz.de/record/169868},
}