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Transcriptome analysis stratifies second-generation non-WNT/non-SHH medulloblastoma subgroups into clinically tractable subtypes

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Abstract

Medulloblastoma (MB), one of the most common malignant pediatric brain tumor, is a heterogenous disease comprised of four distinct molecular groups (WNT, SHH, Group 3, Group 4). Each of these groups can be further subdivided into second-generation MB (SGS MB) molecular subgroups, each with distinct genetic and clinical characteristics. For instance, non-WNT/non-SHH MB (Group 3/4) can be subdivided molecularly into eight distinct and clinically relevant tumor subgroups. A further molecular stratification/summarization of these SGS MB would allow for the assignment of patients to risk-associated treatment protocols. Here, we performed DNA- and RNA-based analysis of 574 non-WNT/non-SHH MB and analyzed the clinical significance of various molecular patterns within the entire cohort and the eight SGS MB, with the aim to develop an optimal risk stratification of these tumors. Multigene analysis disclosed several survival-associated genes highly specific for each molecular subgroup within this non-WNT/non-SHH MB cohort with minimal inter-subgroup overlap. These subgroup-specific and prognostically relevant genes were associated with pathways that could underlie SGS MB clinical-molecular diversity and tumor-driving mechanisms. By combining survival-associated genes within each SGS MB, distinct metagene sets being appropriate for their optimal risk stratification were identified. Defined subgroup-specific metagene sets were independent variables in the multivariate models generated for each SGS MB and their prognostic value was confirmed in a completely non-overlapping validation cohort of non-WNT/non-SHH MB (n = 377). In summary, the current results indicate that the integration of transcriptome data in risk stratification models may improve outcome prediction for each non-WNT/non-SHH SGS MB. Identified subgroup-specific gene expression signatures could be relevant for clinical implementation and survival-associated metagene sets could be adopted for further SGS MB risk stratification. Future studies should aim at validating the prognostic role of these transcriptome-based SGS MB subtypes in prospective clinical trials.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Andrey Korshunov, Daniel Schrimpf, Philipp Sievers, Till Milde, Felix Sahm & Andreas von Deimling

  2. Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany

    Andrey Korshunov, Daniel Schrimpf, Philipp Sievers, Felix Sahm & Andreas von Deimling

  3. Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Andrey Korshunov, Konstantin Okonechnikov, Philipp Sievers, Till Milde, Felix Sahm, David T. W. Jones, Andreas von Deimling, Stefan M. Pfister & Marcel Kool

  4. Division of Pediatric Neuro-Oncology (B062), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

    Konstantin Okonechnikov, Stefan M. Pfister & Marcel Kool

  5. Pediatric Hematology and Oncology and Mildred Scheel Cancer Career Center HaTriCS4, Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Svenja Tonn & Martin Mynarek

  6. Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam and Cancer Center Amsterdam, Amsterdam, The Netherlands

    Jan Koster

  7. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Till Milde

  8. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

    Till Milde & Stefan M. Pfister

  9. Division of Pediatric Glioma Research (B360), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones

  10. Princess Máxima Center for Pediatric Oncology, 3584CS, Utrecht, The Netherlands

    Marcel Kool

Authors
  1. Andrey Korshunov
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  2. Konstantin Okonechnikov
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  3. Daniel Schrimpf
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  4. Svenja Tonn
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  6. Jan Koster
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  7. Philipp Sievers
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  8. Till Milde
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Correspondence to Andrey Korshunov.

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Korshunov, A., Okonechnikov, K., Schrimpf, D. et al. Transcriptome analysis stratifies second-generation non-WNT/non-SHH medulloblastoma subgroups into clinically tractable subtypes. Acta Neuropathol 145, 829–842 (2023). https://doi.org/10.1007/s00401-023-02575-z

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