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@ARTICLE{Okonechnikov:290890,
      author       = {K. Okonechnikov$^*$ and D. Schrimpf$^*$ and J. Koster and
                      P. Sievers$^*$ and T. Milde$^*$ and F. Sahm$^*$ and D. T. W.
                      Jones$^*$ and A. von Deimling$^*$ and S. M. Pfister$^*$ and
                      M. Kool$^*$ and A. Korshunov$^*$},
      title        = {{C}linically unfavorable transcriptome subtypes of
                      non-{WNT}/non-{SHH} medulloblastomas are associated with a
                      predominance in proliferating and progenitor-like cell
                      subpopulations.},
      journal      = {Acta neuropathologica},
      volume       = {147},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2024-01229},
      pages        = {95},
      year         = {2024},
      note         = {#EA:B062#LA:B300#},
      abstract     = {The non-WNT/non-SHH (Grp3/Grp4) medulloblastomas (MBs)
                      include eight second-generation subgroups (SGS; I-VIII) each
                      with distinct molecular and clinical characteristics.
                      Recently, we also identified two prognostically relevant
                      transcriptome subtypes within each SGS MB, which are
                      associated with unique gene expression signatures and
                      signaling pathways. These prognostic subsets may be in
                      connection to the intra-tumoral cell landscape that
                      underlies SGS MB clinical-molecular diversity. Here, we
                      performed a deconvolution analysis of the Grp3/Grp4 MB bulk
                      RNA profiles using the previously identified single-cell
                      RNA-seq reference dataset and focusing on variability in the
                      cellular composition of SGS MB. RNA deconvolution analysis
                      of the Grp3/Grp4 MB disclosed the subgroup-specific
                      neoplastic cell subpopulations. Neuronally differentiated
                      axodendritic GP3-C1 and glutamatergic GP4-C1 subpopulations
                      were distributed within Grp3- and Grp4-associated SGS MB,
                      respectively. Progenitor GP3-B2 subpopulation was prominent
                      in aggressive SGS II MB, whereas photoreceptor/visual
                      perception GP3/4-C2 cell content was typical for SGS III/IV
                      MB. The current study also revealed significant variability
                      in the proportions of cell subpopulations between clinically
                      relevant SGS MB transcriptome subtypes, where unfavorable
                      cohorts were enriched with cell cycle and progenitor-like
                      cell subpopulations and, vice versa, favorable subtypes were
                      composed of neuronally differentiated cell fractions
                      predominantly. A higher than median proportion of
                      proliferating and progenitor cell subpopulations conferred
                      the shortest survival of the Grp3 and Grp 4 MB, and similar
                      survival associations were identified for all SGS MB except
                      SGS IV MB. In summary, the recently identified clinically
                      relevant Grp3/Grp4 MB transcriptome subtypes are composed of
                      different cell populations. Future studies should aim to
                      validate the prognostic and therapeutic role of the
                      identified Grp3/Grp4 MB inter-tumoral cellular
                      heterogeneity. The application of the single-cell techniques
                      on each SGS MB separately could help to clarify the clinical
                      significance of subgroup-specific variability in tumor cell
                      content and its relation with prognostic transcriptome
                      signatures identified before.},
      keywords     = {Humans / Medulloblastoma: genetics / Medulloblastoma:
                      pathology / Medulloblastoma: metabolism / Transcriptome /
                      Cerebellar Neoplasms: genetics / Cerebellar Neoplasms:
                      pathology / Cerebellar Neoplasms: metabolism / Cell
                      Proliferation: genetics / Male / Child / Female / Child,
                      Preschool / Adolescent / Prognosis / Deconvolution (Other) /
                      Medulloblastoma (Other) / Non-WNT/non-SHH (Other) /
                      Prognosis (Other) / Subgroups (Other)},
      cin          = {B062 / HD01 / B300 / B310 / B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)B310-20160331 /
                      I:(DE-He78)B360-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38847845},
      doi          = {10.1007/s00401-024-02746-6},
      url          = {https://inrepo02.dkfz.de/record/290890},
}