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Medulloblastomics revisited: biological and clinical insights from thousands of patients
Open accessAbstract
Medulloblastoma, a malignant brain tumour primarily diagnosed during childhood, has recently been the focus of intensive molecular profiling efforts, profoundly advancing our understanding of biologically and clinically heterogeneous disease subgroups. Genomic, epigenomic, transcriptomic and proteomic landscapes have now been mapped for an unprecedented number of bulk samples from patients with medulloblastoma and, more recently, for single medulloblastoma cells. These efforts have provided pivotal new insights into the diverse molecular mechanisms presumed to drive tumour initiation, maintenance and recurrence across individual subgroups and subtypes. Translational opportunities stemming from this knowledge are continuing to evolve, providing a framework for improved diagnostic and therapeutic interventions. In this Review, we summarize recent advances derived from this continued molecular characterization of medulloblastoma and contextualize this progress towards the deployment of more effective, molecularly informed treatments for affected patients.
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“In order to define a new way to rank medulloblastomas based on histopathological and molecular characteristics, the newly published 2021 WHO classification determinates new subsets below the 4 principal molecular groups: 4 subgroups of SHH and 8 subgroups of non-WNT/non-SHH medulloblastomas [11].”
BackgroundBejenariu, A. E., Milea, A. I., & Sarafoleanu, C. (2023) · Romanian Journal of Rhinology · doi:10.2478/rjr-2023-0004
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Data from Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
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Self-citationData from Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
Borgenvik, A., Holmberg, K. O., Bolin, S., Zhao, M., Savov, V., Rosén, G., Hutter, S., Garancher, A., Rahmanto, A. S., Bergström, T., et al. (2023) · doi:10.1158/0008-5472.c.6514337
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“9% of all embryonal tumors in children and adolescents aged 0–19 years (1) and is one of the most common malignant brain tumors and a leading cause of cancer-related death in children (2).”
BackgroundApplication and Relevance of Organoid/Tumoroid Models in the Context of Pediatric Solid Tumors
Ferreira, B., Peixoto, J., & Lima, J. P. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-15717-2.00011-1
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Pädiatrische Krebserkrankungen
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Tivantinib induces mitotic death in SHH medulloblastoma cell lines.Preprint
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Transcriptional Regulation of Protein Synthesis by Mediator Kinase in MYC-driven MedulloblastomaPreprint
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Additional file 9 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298923
Self-citationAdditional file 8 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298920
Self-citationAdditional file 6 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298914
Self-citationAdditional file 2 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298902
Self-citationAdditional file 7 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298917
Self-citationAdditional file 4 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298908
Self-citationAdditional file 3 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298905
Self-citationAdditional file 5 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298911
Self-citationAdditional file 2 of Clinical and mutational profiles of adult medulloblastoma groups
Wong, G. C.-H., Li, K. K., Wang, W.-W., Liu, A. P. Y., Huang, Q. J., Chan, A. K., Poon, M. F., Chung, N. Y., Wong, Q. H., Chen, H., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13219304
Co-activation of LIN28A and CTNNB1 disturbs cortical neuronal migration and pia mater integrityPreprint
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“Given the diffuse definition of the existing continuum between G3 and G4 in the literature (50), we aimed to compare the molecular features of our proposed G3-G4 subgroup with that of a previous publication that identified three patients as belonging to the potential G3-G4 subgroup using…”
14 Neurosurgical Oncology Neurosurgical oncology
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“This has led to further exploration of stratification of each subgroup into subtypes for the sake of personalized therapies, 14,16 with continued emergence of subtypes within each sub-group in different studies without a consensus on the number of subtypes (7 to 12 subtypes reported within the 4…”
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A cytotoxic gene therapy targeting SOX9-positive therapy-resistant medulloblastoma
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Medulloblastoma chapter - past perspectives and future directions
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“Epigenomic analyses have revealed further heterogeneity within subtypes, identifying four epigenetic subgroups within SHH medulloblastoma and eight within Group 3 and Group 4, each associated with distinct clinical parameters [2,9–11].”
Growth hormone replacement therapy does not predict relapse across medulloblastoma subgroups
Caballero, M., Wilhelmsson, M., Wasserman, J. D., McKeown, T., Tsang, D. S., Tabori, U. Y., Huang, A., Liu, A. P. Y., Das, A., Bennett, J., et al. (2025) · Neuro-Oncology Pediatrics · doi:10.1093/neuped/wuaf006
Hidden-driver inference reveals synergistic brain-penetrant therapies for medulloblastomaPreprint
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“Most survivors experience long-term sequelae caused by highly aggressive multimodal therapies 1 – 3 .”
Self-citationA pathway-informed mutual exclusivity framework to detect genetic interactions in pediatric cancer
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“2a, b).”
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Additional file 1 of Group-specific cellular metabolism in Medulloblastoma
Funke, V. L. E., Walter, C., Melcher, V., Wei, L., Sandmann, S., Hotfilder, M., Varghese, J., Jäger, N., Kool, M., Jones, D. T. W., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23298899
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Additional file 1 of Mitochondrial DNA mutations in Medulloblastoma
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Additional file 1 of Clinical and mutational profiles of adult medulloblastoma groups
Wong, G. C.-H., Li, K. K.-W., Wang, W.-W., Liu, A. P.-Y., Huang, Q. J., Chan, A. K.-Y., Poon, M. F.-M., Chung, N. Y., Wong, Q. H., Chen, H., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13219301
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Joshi, K., Yuan, M., Katsushima, K., Saulnier, O., Ray, A., Amankwah, E., Stapleton, S. L., Jallo, G. I., Taylor, M. D., Eberhart, C. G., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26943624
Joshi, K., Yuan, M., Katsushima, K., Saulnier, O., Ray, A., Amankwah, E., Stapleton, S. L., Jallo, G. I., Taylor, M. D., Eberhart, C. G., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26943627
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Joshi, K., Yuan, M., Katsushima, K., Saulnier, O., Ray, A., Amankwah, E., Stapleton, S. L., Jallo, G. I., Taylor, M. D., Eberhart, C. G., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26943621
Additional file 2 of Mitochondrial DNA mutations in Medulloblastoma
Funke, V. L. E., Sandmann, S., Melcher, V., Seggewiß, J., Horvath, J. E., Jäger, N., Kool, M., Jones, D. T. W., Pfister, S. M., Milde, T., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26606920
Self-citationJoshi, K., Yuan, M., Katsushima, K., Saulnier, O., Ray, A., Amankwah, E., Stapleton, S. L., Jallo, G. I., Taylor, M. D., Eberhart, C. G., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26943615
Distinct cMET inhibitors uncover pharmacological heterogeneity in SHH medulloblastoma cell lines
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“According to the 2021 World Health Organization (WHO) classification of CNS tumours, MB includes four genetically distinct subgroups: Wingless (WNT), Sonic Hedgehog (SHH, with TP53-wildtype and TP53-mutant sub-types), Group 3 (G3), and Group 4 (G4) [2].”
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Immunotherapy approaches for the treatment of relapsed or progressive medulloblastoma
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The future of targeted therapies for pediatric central nervous system tumors
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“7,93,94 Of all pediatric CNS embryonal tumors, the most experience in the use of targeted therapies is for SHH medulloblastomas.”
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Decoding the immune microenvironment: precision immunotherapy for medulloblastoma subtypes
Li, M., Peng, J., Chen, C., & Hu, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1714134
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Proteomic and Metabolomic Analysis of PCK2-Dependent Alterations in Group 3 Medulloblastoma Cells
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A run length weighted mean difference approach for enhanced feature selection
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Immune Cell Therapy Promises More Effective Cure for Medulloblastoma
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“These subgroups have been further subdivided into a total of 13 subtypes with distinct molecular and clinical features [69,70].”
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“Despite advances in molecular subtyping for risk assessment, outcomes remain poor, especially for patients with MYC amplification [3].”
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Paediatric therapeutic development workshop on medulloblastoma
Montiel-Equihua, C., Baxter, J. S., Molenaar, J. J., Zubiaur, I. A., Abbou, S. D., Anderson, J., André, N., Ayrault, O., Blanc, P., Carpenter, N., et al. (2026) · British Journal of Cancer · doi:10.1038/s41416-026-03533-8
“SHH-activated medulloblastomas SHH-activated medulloblastomas arise from granule cell progenitors and granule cells in the upper rhombic lip [22 – 24] and are characterised by gene mutations or copy number alterations in the SHH pathway.”
Self-citationZhang, X., 杜来玲, Tian, K., Chen, L., & Li, X. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1909580
“Epigenetic dysregulation is one of the central determinants of MB biology regarding tumor initiation, progression, cellular heterogeneity, and therapeutic response (Hovestadt et al., 2020; Northcott et al., 2019).”
InfluentialDivergent medulloblastoma chromatin states disclose KDM2B as a selective dependency
Tao, R., Erkek, S., Xu, B., Matsui, Y., Mittal, P., Smith, K. S., Li, Y., Filipovic, D., Xu, R., Gao, Q., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02745-1
Self-citationErtekin, M., Temuroglu, A., Aksoy, G. R., Taskapilioglu, M. O., & Sevinir, B. B. (2026) · Child s Nervous System · doi:10.1007/s00381-026-07496-2
“The use of molecular stratification into four groups (WNT, SHH, Group 3, Group 4) has considerably advanced prognostication [7–10].”
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BindingDB Entry 50015598: Medulloblastoma drugs in development: Current leads, trials and drawbacks.
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Metadata
- Authors
- Hovestadt, V., Ayrault, O., Swartling, F. J., Robinson, G. W., Pfister, S. M., & Northcott, P. A.
- Affiliations
- Broad Institute (US)
- Université Paris-Sud (FR)
- Uppsala University (SE)
- St. Jude Children's Research Hospital (US)
- German Cancer Research Center (DE)
- Corresponding author
- Northcott, Paul A.
- ORCID
- Venue
- Nature Reviews Cancer
- Published
- 2019-12-09
- Volume
- 20
- Issue
- 1
- Pages
- 42-56
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC9113832
- OpenAlex
- W2991944835
- Cited by
- 271
- References
- 155
- Citations by year
- 2026: 26 · 2025: 47 · 2024: 44 · 2023: 53 · 2022: 36 · 2021: 45 · 2020: 17 · 2019: 1
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- National Cancer Institute (R01CA232143)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- medulloblastoma, molecular subtypes, single-cell profiling, genomic profiling, epigenetic profiling, gene expression profiling, proteomic profiling, tumor heterogeneity, tumor recurrence, pediatric brain tumors, targeted therapy, diagnosis
- MeSH terms
- Animals, Combined Modality Therapy, Disease Susceptibility, Humans, Medulloblastoma, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Recurrence, Biomarkers, Tumor, Treatment Outcome, Disease Management, Genomics, Molecular Diagnostic Techniques, Proteomics, Genetic Association Studies, Epigenomics, Tumor Microenvironment
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