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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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Cerebrospinal fluid liquid biopsies for medulloblastoma
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“Medulloblastoma (MB) is a heterogeneous disease comprised of a few distinct clinical-molecular subtypes [3, 10, 20, 28].”
BackgroundInfluentialSelf-citationThe pivotal role of irradiation‐induced apoptosis in the pathogenesis and therapy of medulloblastoma
Richard, S. A. (2024) · Cancer Reports · doi:10.1002/cnr2.2048 · Cited by 7
“20,21 Interestingly, these subtypes exhibit diverse responses to current therapy, with the worse survival rates for MYC-amplified G3 such as G3 γ or G3, G4 or subtype II also known as G3-II and TP53-mutated SHH (SHH α ) or outstanding survival for WNT MB. 20,21 In addition, the long-term survival…”
BackgroundSonic hedgehog medulloblastomas are dependent on Netrin-1 for survival
Talbot, J., Fombonne, J., Torrejon-Diaz, J., Babcock, B. R., McSwain, L., Rama, N., Severini, L. L., Bonerandi, E., Marsaud, V., Bernardi, F., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59612-6 · Cited by 7
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Self-citationClinical and Molecular Features in Medulloblastomas Subtypes in Children in a Cohort in Taiwan
Wu, K.-S., Sung, S., Huang, M., Lin, Y., Chang, C., Fang, C., Wong, T., Chen, H., & Tsai, M. (2022) · Cancers · doi:10.3390/cancers14215419 · Cited by 7
“The highest metastatic rate presented in SHH β in our and other studies [2,6].”
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Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma
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“Several studies have highlighted the potential of machine learning in sleep research, offering insights into patterns that may not be immediately apparent to clinicians or traditional models [19]–[21].”
BackgroundIdentification of PBK as a hub gene and potential therapeutic target for medulloblastoma
Deng, Y., Wen, H., Yang, H., Zhu, Z., Huang, Q., Bi, Y.-W., Wang, P., Zhou, M., Guan, J., Zhang, W., et al. (2022) · Oncology Reports · doi:10.3892/or.2022.8336 · Cited by 8
“The MB classification process has evolved from relying solely on histopathological features to the integration of molecular characteristics (2).”
BackgroundSystematic analysis of MCM3 in pediatric medulloblastoma via multi-omics analysis
Cao, L., Zhao, Y., Liang, Z., Yang, J., Wang, J., Tian, S., Wang, Q., Wang, B., Zhao, H., Jiang, F., et al. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.815260 · Cited by 7
“Medulloblastoma (MB), the leading cause of cancer-related death in children, is one of the most common pediatric brain tumors (Hovestadt et al., 2020).”
BackgroundAhmad, Z., Rahim, S., Abdul‐Ghafar, J., Chundriger, Q., & Din, N. U. (2023) · International Journal of General Medicine · doi:10.2147/ijgm.s394872 · Cited by 7
Moreno, D. A., Bonatelli, M., Antoniazzi, A. P., de Paula, F. E., Leal, L. F., Garcia, F. A. D. O., de Paula, A. E., Teixeira, G. R., Santana, I. V. V., Saggioro, F. P., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1237170 · Cited by 7
“The wingless (WNT)-activated group accounts for 10% of all medulloblastomas, is commonly observed in children older than 4 years, in an equal proportion of boys and girls, and usually shows no metastasis at diagnosis (3).”
Reznicek, J., Sharifai, N., Jamshidi, P., Wadhwani, N. R., & Ahrendsen, J. T. (2023) · Cytopathology · doi:10.1111/cyt.13350 · Cited by 6
Bonifacio-Mundaca, J., Casavilca-Zambrano, S. A., Desterke, C., Casafont, Í., & Mata-Garrido, J. (2025) · Biomedicines · doi:10.3390/biomedicines13081898 · Cited by 6
“Epigenetically, MB exhibits distinct DNA methylation profiles, histone modification signatures, and chromatin remodeling activities that mirror developmental origins and therapeutic vulnerabilities [26,43,47].”
WNT‐activated, MYC ‐amplified medulloblastoma displaying intratumoural heterogeneity
Green, S. T., Hoover, T., Doss, D., Davidow, K. A., Walter, A. W., Cottrell, C. E., & Mahapatra, S. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12945 · Cited by 4
“In our CTNNB1 mutation is a hallmark of WNT-activated tumours [3, 4, 13].”
BackgroundJoshi, K., Yuan, M., Katsushima, K., Saulnier, O., Ray, A., Amankwah, E. K., Stapleton, S. L., Jallo, G. I., Taylor, M. D., Eberhart, C. G., et al. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01848-2 · Cited by 6
“Different MB subgroups have different etiologies and cells of origin [4], and the resulting tumors progress differently, requiring personalized management.”
BackgroundERAP1 as an emerging therapeutic target for medulloblastoma
Bufalieri, F., Fruci, D., & Marcotullio, L. D. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.09.005 · Cited by 6
Prajapati, H. P., & Kannaujia, S. K. (2022) · Surgical Neurology International · doi:10.25259/sni_102_2022 · Cited by 6
Clinico-Radiological Outcomes in WNT-Subgroup Medulloblastoma
Mani, S., Chatterjee, A., Dasgupta, A., Shirsat, N. V., Pawar, A., Epari, S., Sahay, A., Sahu, A., Moiyadi, A. V., Prasad, M., et al. (2024) · Diagnostics · doi:10.3390/diagnostics14040358 · Cited by 5
“…to perform large-scale integrative clustering analysis combining DNA methylation and gene-expression profiling to identify further sub-types within each broad molecular subgroup [24–26] resulting in a consensus definition of 12 subtypes of MB in second-generation molecular subgrouping [27].”
BackgroundAlshawli, A. S., Wurdak, H., Wood, I. C., & Ladbury, J. E. (2020) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.1429 · Cited by 5
“They were classified into the four medulloblastoma (WNT, SHH, Group 3, and Group 4) subgroups and the 12 subtypes based on their genetic and methylation profiles (Hovestadt et al., 2019).”
BackgroundMethodResultInfluentialHarnessing brain development to understand brain tumours
Marino, S., & Gilbertson, R. J. (2021) · Development · doi:10.1242/dev.193342 · Cited by 7
Evolution of neurosurgical advances and nuances in medulloblastoma therapy
Rechberger, J. S., Power, E. A., DeCuypere, M. G., & Daniels, D. J. (2023) · Child s Nervous System · doi:10.1007/s00381-023-06239-x · Cited by 5
“…molecular subgroups established by consensus are still commonly used (WNT, SHH, Group 3, Group 4), they are represented in a slightly different manner in WHO CNS5: SHH tumors are further divided on the basis of TP53 status and non-WNT/non-SHH tumors comprise both group 3 and group 4 [23, 57, 58].”
Mitoxantrone alters CD24/Siglec-10 expression in malignant brain tumor models
Kopecký, J., Pérez, J. E., Jonathan, S., Milos, T., Kwanyuen, P., Biskupiak, J., Visse, E., de Oliveira, K. G., Hugo Talbot, A., Cerezo-Magaña, M., et al. (2026) · Scientific Reports · doi:10.1038/s41598-026-37588-7 · Cited by 6
“Studies of several pathological entities where blocking of CD24/Siglec-10 by antibodies or small molecules was investigated as monotherapy, show modest outcome improvement but is substantially potentiated by simultaneous blockage of other immunosuppressive mechanisms 18–20,60 Further research and clinical trials are n…”
InfluentialGao, X., Zhuang, Q., Li, Y., Li, G., Huang, Z., Chen, S., Sun, S., Yang, H., Jiang, L., & Mao, Y. Q. (2024) · Advanced Science · doi:10.1002/advs.202309554 · Cited by 4
Li, Q., Jia, Y., Tang, B., Yang, H., Yang, Q., Luo, X., & Pan, Y. (2023) · Biomarkers · doi:10.1080/1354750x.2023.2276670 · Cited by 5
“…that occur in the shh signaling pathway are deletions and loss-of-function mutations in GNAS , PTCH1 , GPR161 , mutations that activate SMO or amplifications of GLI1 , GLI2 and MYCN (luo et al. 2021). less than 10% of the Group 3 or Group 4 MBs have a clear driver mutation (hovestadt et al. 2020).”
BackgroundGupta, T., Mani, S., Chatterjee, A., Dasgupta, A., Epari, S., & Chinnaswamy, G. (2024) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2024.2357807 · Cited by 5
Immunohistochemical Surrogates for Molecular Stratification in Medulloblastoma
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Using evolutionary constraint to define novel candidate driver genes in medulloblastoma
Roy, A., Sakthikumar, S., Kozyrev, S. V., Nordin, J., Pensch, R., Mäkeläinen, S., Pettersson, M. E., Karlsson, E. K., Lindblad‐Toh, K., Forsberg‐Nilsson, K., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2300984120 · Cited by 5
Activity-Based Nanoprobes for Multiscale Functional Analysis of Proteases in Medulloblastomas
Yu, Y., Wang, Y., Peng, Y., Liu, Y., Li, M., Chen, R., Zhang, C., & Zhang, K. (2025) · ACS Sensors · doi:10.1021/acssensors.5c02028 · Cited by 4
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“This manuscript by Wang et al. investigated the role of CDK8 in MYC-driven medulloblastoma, particularly focused on Group 3 MB, which had a notably poor prognosis.”
Han, B., Wang, Y., Yue, S., Zhang, Y.-H., Kuang, L., Gao, B., Wang, Y., Zhang, Z., Pu, X., Wang, X.-F., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.176044 · Cited by 4
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Mitochondrial DNA mutations in Medulloblastoma
Funke, V. L. E., Sandmann, S., Melcher, V., Seggewiß, J., Horvath, J. E., Jäger, N., Kool, M., Jones, D., Pfister, S. M., Milde, T., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01602-0 · Cited by 4
“Four established MB groups, namely WNT, SHH, group 3 (G3) and group 4 (G4), differ in molecular driver events and patient outcomes [1].”
BackgroundSelf-citationLukoseviciute, M., Need, E., Birgersson, M., Dalianis, T., & Kostopoulou, O. N. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117500 · Cited by 4
The pivotal role of autophagy in the pathogenesis and therapy of medulloblastoma
Richard, S. A. (2024) · Future Oncology · doi:10.1080/14796694.2024.2420629 · Cited by 4
Nanopore sequencing as a cutting-edge technology for medulloblastoma classification
Filser, M., Torrejon-Diaz, J., Merchadou, K., Dufour, C., Girard, E., Bourneix, C., Lemaître, E., Gharsalli, T., Brillet, R., Wong, J., et al. (2024) · Neuro-Oncology · doi:10.1093/neuonc/noae279 · Cited by 4
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Gussow, A. B., Koonin, E. V., & Auslander, N. (2021) · NAR Cancer · doi:10.1093/narcan/zcab017 · Cited by 5
“Several methods have been developed to identify complex combinations of mutations that correspond to interaction networks (55,56,57) and/or can be used for cancer subtype clustering (9,58,59), but to our knowledge, these precise methods have not been directly harnessed towards survival prediction, despite the observat…”
The RACE to Develop New Targeted Therapies for Children With CNS Tumors
Fletcher, E. P., Burckart, G. J., Robinson, G. W., Reaman, G. H., & Stewart, C. F. (2020) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1937 · Cited by 4
Self-citationHigh cellular plasticity state of medulloblastoma local recurrence and distant dissemination
Liu, H., Zhang, J., Wang, Z., Wang, W., Han, D., Chen, X., Su, Y., Zhang, J., Daniels, C. E., Saulnier, O., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101914 · Cited by 3
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“Recently, various mouse models (orthotopic, transgenic, and somatic gene transfer animals) have been used to demonstrate that stem/progenitor cells can be successfully transformed recapitulating the molecular and phenotypic characteristics of MYCN-driven SHH MB orMYCN- orMYC-driven Group 3MB (Hovestadt et al., 2020).”
BackgroundInfluentialIn silico drug sensitivity predicts subgroup-specific therapeutics in medulloblastoma patients
Jermakowicz, A. M., Ruiz, L. C., Chu, J., Jangde, N., Suter, R. K., Kadan‐Lottick, N. S., Hanson, D. J., & Ayad, N. G. (2025) · Scientific Reports · doi:10.1038/s41598-025-26411-4 · Cited by 3
An Inbred Ecosystem that Supports Medulloblastoma
de Pablos-Aragoneses, A., & Valiente, M. (2020) · Immunity · doi:10.1016/j.immuni.2020.02.010 · Cited by 3
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“In recent times, a number of papers have begun to explain the role of proteomics and post-transcriptional modifications in shaping the behavior, aggressiveness, and sensitivity to treatments of MB [6, 7].”
BackgroundJones, C., Straathof, K. C. M., Fouladi, M., Hargrave, D. R., Prados, M. D., Resnick, A. C., Doz, F., Jones, D., & Mueller, S. C. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1167082 · Cited by 3
Insights into the molecular roles of FOXR2 in the pathology of primary pediatric brain tumors
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Cola, A. D., Foss, A., Gilbertson, R. J., & Pathania, M. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-062722-034650 · Cited by 3
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“For a comprehensive overview of molecular groups and histological types, see Shih and Koeller [16], Cassia et al. [17], Northcott et al. [1] or Hovestadt et al. [18].”
Approaches to supratentorial brain tumours in children
Sepúlveda, F., Opipari, R. S., Coppola, F., Ramaglia, A., Mankad, K., Alves, C., Bison, B., & Löbel, U. (2024) · Neuroradiology · doi:10.1007/s00234-024-03398-9 · Cited by 3
Crossing the Blood-Brain Barrier: Advancing Immunotherapy for Pediatric Brain Tumors
Mortezaei, N. T., Habibzadeh, A., Rahimian, Z., Boushehri, S., Pourbakhtyaran, E., Savoji, A. B., & Farid, A. S. (2024) · Interdisciplinary cancer research · doi:10.1007/16833_2024_400 · Cited by 3
Role of liquid biopsy in central nervous system tumors
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“SHH-MB tumours constitute the pre-dominant tumour type in young children (<3 years of age) and adults (>17 years of age) (Hovestadt et al., 2020; Northcott et al., 2011).”
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Shi, X., Liu, S., Sun, X., Li, Y., & Jiang, M. (2025) · Advances in Radiation Oncology · doi:10.1016/j.adro.2025.101796 · Cited by 2
“Despite the subsequent emergence of more re fi ned subtypes, 10-12 the classic 4 subtypes remain the cornerstone and are more common and easier to apply in clinical applications.”
Navolić, J., Hawass, S., Moritz, M., Hahn, J., Middelkamp, M., Gocke, A., Dottermusch, M., Schumann, Y., Ruck, L., Krisp, C., et al. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101037 · Cited by 2
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“Medulloblastoma (MB) is one of the most common malignant tumors in the cerebella of children [ 1 ].”
Euzébio, M. F., Silva, F. L. T., Hoffmann, I. L., Ruas, J. S., Kido, L. A., de Lima, D. G., Queiróz, L. D. S., Cardinalli, I. A., Seidinger, A. L., Nascimento, S., et al. (2025) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.70041 · Cited by 2
“Therefore, from both prognostic and therapeutic perspectives, the diagnostic refinement offered by molecular classification is especially valuable for medulloblastomas [24, 43, 44].”
Soares-Ferreira, B., Peixoto, J., Ferro, A., Esteves, B., Pinheiro, J., da Silva, R. L., Pereira, J., Oliveira, J., Paula, A. D. C., Zhu, Y., et al. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01151-w · Cited by 2
“5c) 27 .”
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“Group 4 tumors represent the most common molecular subgroup, comprising 35–40% of all cases [65].”
Skitchenko, R. K., Dinikina, Y. V., Smirnov, S., Krapivin, M., Smirnova, А. Y., Morgacheva, D. A., & Artomov, M. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2022.1085947 · Cited by 2
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The phosphorylation of PHF5A by TrkA-ERK1/2-ABL1 cascade regulates centrosome separation
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“Medulloblastoma has been categorized into four subgroups named Wnt, Shh, Goup3, and Group4 [30].”
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Genomic landscape of medulloblastoma subtypes in an Asian cohort
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AZIN1 level is increased in medulloblastoma and correlates with c-Myc activity and tumor phenotype
Sesen, J., Martinez, T., Busatto, S., Poluben, L., Nassour, H., Stone, C. E., Ashok, K., Moses, M. A., Smith, E. R., & Ghalali, A. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03274-1 · Cited by 3
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A SHHecret target of relapsed medulloblastoma: Astrocytes
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Diagnosis and management of central nervous system embryonal tumors in the molecular era
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Imaging Embryonal Tumors of the Central Nervous System
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Cell-state plasticity drives heterogeneity in Group 3/4 medulloblastomaPreprint
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“Medulloblastoma in the WNT group rarely metastasize and tend to have the best prognosis; SHH and G4 tumors generally have an intermediate prognosis (4, 5); and G3 tumors are associated with greater malignancy and more frequent metastatic dissemination (5, 6).”
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“Medulloblastoma is a grade IV CNS tumor that develops mainly in the cerebellum of children under 10 years old [14–16].”
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“…analysis of the Cavalli et al. [8] and P fi ster [7] cohorts highlighted highly signi fi cant associations between EIF4EBP1 and MYC mRNA levels in the MYC -ampli fi ed MB subgroups, namely Group 3 subgroup gamma (corresponding mainly to subtype II [42]) ([r] 0.704, p value < 0.0001; Supplementary Fig.”
InfluentialOld Tools in a New Era: The Continued Relevance of Chemotherapy in Pediatric Neuro-Oncology
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“Molecular characterization of MB using various next-generation sequencing techniques, transcriptome studies, and DNA methylation studies has classified MB now into four subgroups, WNT, SHH, Group 3, and Group 4 [21–26].”
Challenges and opportunities for treatment of medulloblastoma
Mehta, M., Somasundaram, D. B., Munshi, A., & Ramesh, R. (2025) · Advances in cancer research · doi:10.1016/bs.acr.2025.06.006 · Cited by 1
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“MB is characterized as a small round blue cell tumor of the cerebellum that can disseminate throughout the CNS, often complicating treatment outcomes [3,4].”
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Detection of structural DNA variants in medulloblastomas using optical genome mapping
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“In line with previous research [28, 40], MB WNT tumors presented with mostly balanced genomes upon OGM analysis.”
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AMBRA1 enhances Sonic Hedgehog signaling during cerebellar development and in medulloblastoma
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Intracranial Tumors in the First Year of Life
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“21,22 2 | MATERIALS AND METHODS”
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The intersections between neuroscience and medulloblastoma
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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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