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@ARTICLE{Mynarek:182882,
      author       = {M. Mynarek and D. Obrecht and M. Sill$^*$ and D. Sturm$^*$
                      and K. Kloth-Stachnau and F. Selt$^*$ and J. Ecker$^*$ and
                      K. von Hoff and B.-O. Juhnke and T. Goschzik and T. Pietsch
                      and M. Bockmayr and M. Kool$^*$ and A. von Deimling$^*$ and
                      O. Witt$^*$ and U. Schüller and M. Benesch and N. U. Gerber
                      and F. Sahm$^*$ and D. Jones$^*$ and A. Korshunov$^*$ and S.
                      Pfister$^*$ and S. Rutkowski and T. Milde$^*$},
      title        = {{I}dentification of low and very high-risk patients with
                      non-{WNT}/non-{SHH} medulloblastoma by improved
                      clinico-molecular stratification of the {HIT}2000 and
                      {I}-{HIT}-{MED} cohorts.},
      journal      = {Acta neuropathologica},
      volume       = {145},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2022-02988},
      pages        = {97-112},
      year         = {2023},
      note         = {#LA:B310# / 2023 Jan;145(1):97-112},
      abstract     = {Molecular groups of medulloblastoma (MB) are well
                      established. Novel risk stratification parameters include
                      Group 3/4 (non-WNT/non-SHH) methylation subgroups I-VIII or
                      whole-chromosomal aberration (WCA) phenotypes. This study
                      investigates the integration of clinical and molecular
                      parameters to improve risk stratification of non-WNT/non-SHH
                      MB. Non-WNT/non-SHH MB from the HIT2000 study and the
                      HIT-MED registries were selected based on availability of
                      DNA-methylation profiling data. MYC or MYCN amplification
                      and WCA of chromosomes 7, 8, and 11 were inferred from
                      methylation array-based copy number profiles. In total, 403
                      non-WNT/non-SHH MB were identified, 346/403 $(86\%)$ had a
                      methylation class family Group 3/4 methylation score
                      (classifier v11b6) ≥ 0.9, and 294/346 $(73\%)$ were
                      included in the risk stratification modeling based on Group
                      3 or 4 score (v11b6) ≥ 0.8 and subgroup I-VIII score
                      $(mb_g34)$ ≥ 0.8. Group 3 MB (5y-PFS, survival estimation
                      ± standard deviation: 41.4 ± $4.6\%;$ 5y-OS: 48.8 ±
                      $5.0\%)$ showed poorer survival compared to Group 4 (5y-PFS:
                      68.2 ± $3.7\%;$ 5y-OS: 84.8 ± $2.8\%).$ Subgroups II
                      (5y-PFS: 27.6 ± $8.2\%)$ and III (5y-PFS: 37.5 ± $7.9\%)$
                      showed the poorest and subgroup VI (5y-PFS: 76.6 ±
                      $7.9\%),$ VII (5y-PFS: 75.9 ± $7.2\%),$ and VIII (5y-PFS:
                      66.6 ± $5.8\%)$ the best survival. Multivariate analysis
                      revealed subgroup in combination with WCA phenotype to best
                      predict risk of progression and death. The integration of
                      clinical (age, M and R status) and molecular (MYC/N,
                      subgroup, WCA phenotype) variables identified a low-risk
                      stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk
                      stratum with a 5y-PFS of 29 ± $6.1\%.$ Validation in an
                      international MB cohort confirmed the combined
                      stratification scheme with 82.1 ± $6.0\%$ 5y-PFS in the low
                      and 47.5 ± $4.1\%$ in very high-risk groups, and
                      outperformed the clinical model. These newly identified
                      clinico-molecular low-risk and very high-risk strata,
                      accounting for $6\%,$ and $21\%$ of non-WNT/non-SHH MB
                      patients, respectively, may improve future treatment
                      stratification.},
      keywords     = {Group 3/4 (Other) / Medulloblastoma (Other) /
                      Non-WNT/non-SHH (Other) / Risk stratification (Other)},
      cin          = {B360 / B310 / B062 / HD01 / B300},
      ddc          = {610},
      cid          = {I:(DE-He78)B360-20160331 / I:(DE-He78)B310-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B300-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36459208},
      doi          = {10.1007/s00401-022-02522-4},
      url          = {https://inrepo02.dkfz.de/record/182882},
}