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@ARTICLE{Schwalbe:293955,
      author       = {E. C. Schwalbe and J. C. Lindsey and M. Danilenko and R. M.
                      Hill and S. Crosier and S. L. Ryan and D. Williamson and J.
                      Castle and D. Hicks and M. Kool$^*$ and T. Milde$^*$ and A.
                      Korshunov$^*$ and S. M. Pfister$^*$ and S. Bailey and S. C.
                      Clifford},
      title        = {{M}olecular and clinical heterogeneity within {MYC}-family
                      amplified medulloblastoma is associated with survival
                      outcomes: {A} multicenter cohort study.},
      journal      = {Neuro-Oncology},
      volume       = {27},
      number       = {1},
      issn         = {1522-8517},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2024-02020},
      pages        = {222–236},
      year         = {2025},
      note         = {Volume 27, Issue 1, January 2025, Pages 222–236},
      abstract     = {MYC/MYCN are the most frequent oncogene amplifications in
                      medulloblastoma (MB) and its primary biomarkers of high-risk
                      (HR) disease. However, while many patients' MYC(N)-amplified
                      tumors are treatment-refractory, some achieve long-term
                      survival. We therefore investigated clinicobiological
                      heterogeneity within MYC(N)-amplified MB and determined its
                      relevance for improved disease management.We characterized
                      the clinical and molecular correlates of MYC- (MYC-MB; n =
                      64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from
                      >1600 diagnostic cases.Most MYC-MBs were molecular group 3
                      (46/58; $79\%$ assessable) and aged ≥3 years at diagnosis
                      (44/64 $[69\%]).$ We identified a 'canonical' very high-risk
                      (VHR) MYC-amplified group (n = 51/62; $82\%)$ with dismal
                      survival irrespective of treatment $(11\%$ 5-year
                      progression-free survival [PFS]), defined by co-occurrence
                      with ≥1 additional established risk factor(s) (subtotal
                      surgical-resection [STR], metastatic disease, LCA
                      pathology), and commonly group 3/4 subgroup 2 with a high
                      proportion of amplified cells. The majority of remaining
                      noncanonical MYC-MBs survived (i.e. non-group 3/group 3
                      without other risk features; 11/62 $(18\%);$ $61\%$ 5-year
                      PFS). MYCN survival was primarily related to molecular
                      group; MYCN-amplified SHH MB, and group 3/4 MB with
                      additional risk factors, respectively defined VHR and HR
                      groups (VHR, $39\%$ [35/89]; $20\%$ 5-year PFS/HR, $33\%$
                      [29/89]; $46\%$ 5-year PFS). Twenty-two out of 35 assessable
                      MYCN-amplified SHH tumors harbored TP53 mutations; 9/12
                      $(75\%)$ with data were germline. MYCN-amplified group 3/4
                      MB with no other risk factors $(28\%;$ 25/89) had $70\%$
                      5-year PFS.MYC(N)-amplified MB displays significant
                      clinicobiological heterogeneity. Diagnostics incorporating
                      molecular groups, subgroups, and clinical factors enable
                      their risk assessment. VHR 'canonical' MYC tumors are
                      essentially incurable and SHH-MYCN-amplified MBs fare
                      extremely poorly $(20\%$ survival at 5 years); both require
                      urgent development of alternative treatment strategies.
                      Conventional risk-adapted therapies are appropriate for more
                      responsive groups, such as noncanonical MYC and non-SHH-MYCN
                      MB.},
      keywords     = {MYC amplification (Other) / MYCN amplification (Other) /
                      medulloblastoma (Other) / survival (Other)},
      cin          = {B062 / HD01 / B300 / B310},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)B310-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39377358},
      doi          = {10.1093/neuonc/noae178},
      url          = {https://inrepo02.dkfz.de/record/293955},
}