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Dissecting the genomic complexity underlying medulloblastoma
Open accessAbstract
Medulloblastoma is the most common brain tumour in children; using whole-genome sequencing of tumour samples the authors show that the clinically challenging Group 3 and 4 tumours can be tetraploid, and reveal the expression of the first medulloblastoma fusion genes identified. Medulloblastoma is the most common malignant brain tumour in children. Four papers published in the 2 August 2012 issue of Nature use whole-genome and other sequencing techniques to produce a detailed picture of the genetics and genomics of this condition. Notable findings include the identification of recurrent mutations in genes not previously implicated in medulloblastoma, with significant genetic differences associated with the four biologically distinct subgroups and clinical outcomes in each. Potential avenues for therapy are suggested by the identification of targetable somatic copy-number alterations, including recurrent events targeting TGFβ signalling in Group 3, and NF-κB signalling in Group 4 medulloblastomas. Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity1. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified2,3. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens4. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis2. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges2,3,5. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour–normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
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Metadata
- Authors
- Jones, D. T. W., Jäger, N., Kool, M., Zichner, T., Hutter, B., Sultan, M., Cho, Y.-J., Pugh, T. J., Hovestadt, V., Stütz, A. M., Rausch, T., Warnatz, H.-J., Ryzhova, M., Bender, S., Sturm, D., Pleier, S., Cin, H., Pfaff, E., Sieber, L., Wittmann, A., Remke, M., Witt, H., Hutter, S., Tzaridis, T., Weischenfeldt, J., Raeder, B., Avci, M., Amstislavskiy, V., Zapatka, M., Weber, U. D., Wang, Q., Lasitschka, B., Bartholomae, C. C., Schmidt, M., von Kalle, C., Ast, V., Lawerenz, C., Eils, J., Kabbe, R., Benes, V., van Sluis, P., Koster, J., Volckmann, R., Shih, D., Betts, M. J., Russell, R. B., Coco, S., Paolo Tonini, G., Schüller, U., Hans, V., Graf, N., Kim, Y.-J., Monoranu, C., Roggendorf, W., Unterberg, A., Herold-Mende, C., Milde, T., Kulozik, A. E., von Deimling, A., Witt, O., Maass, E., Rössler, J., Ebinger, M., Schuhmann, M. U., Frühwald, M. C., Hasselblatt, M., Jabado, N., Rutkowski, S., von Bueren, A. O., Williamson, D., Clifford, S. C., McCabe, M. G., Peter Collins, V., Wolf, S., Wiemann, S., Lehrach, H., Brors, B., Scheurlen, W., Felsberg, J., Reifenberger, G., Northcott, P. A., Taylor, M. D., Meyerson, M., Pomeroy, S. L., Yaspo, M.-L., Korbel, J. O., Korshunov, A., Eils, R., Pfister, S. M., & Lichter, P.
- Affiliations
- German Cancer Research Center (DE)
- European Molecular Biology Laboratory (DE)
- Max Planck Institute for Molecular Genetics (DE)
- Stanford University (US)
- Broad Institute (US)
- Burdenko Neurosurgery Institute (RU)
- Amsterdam UMC Location University of Amsterdam (NL)
- Hospital for Sick Children (CA)
- Heidelberg University (DE)
- Ospedale Policlinico San Martino (IT)
- Institut für Neuropathologie (DE)
- Evangelisches Krankenhaus Bielefeld (DE)
- Universitätsklinikum des Saarlandes (DE)
- University of Würzburg (DE)
- University Hospital Heidelberg (DE)
- Olgahospital (DE)
- University Medical Center Freiburg (DE)
- University Children's Hospital Tübingen (DE)
- University Hospital Münster (DE)
- McGill University Health Centre (CA)
- University Medical Center Hamburg-Eppendorf (DE)
- Royal Victoria Infirmary (GB)
- University of Cambridge (GB)
- Cnopf´sche Kinderklinik (DE)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Eils, Roland
- Pfister, Stefan M.
- Lichter, Peter
- ORCID
- Jones, David T. W.
- Jäger, Natalie
- Kool, Marcel
- Zichner, Thomas
- Hutter, Barbara
- Sultan, Marc
- Cho, Yoon-Jae
- Pugh, Trevor J.
- Hovestadt, Volker
- Stütz, Adrian M.
- Rausch, Tobias
- Warnatz, Hans-Jörg
- Ryzhova, Marina
- Sturm, Dominik
- Pfaff, Elke
- Remke, Marc
- Witt, Hendrik
- Hutter, Sonja
- Tzaridis, Theophilos
- Weischenfeldt, Joachim
- Raeder, Benjamin
- Amstislavskiy, Vyacheslav
- Zapatka, Marc
- Wang, Qi
- Schmidt, Manfred
- Ast, Volker
- Kabbe, Rolf
- Volckmann, Richard
- Shih, David
- Betts, Matthew J.
- Russell, Robert B.
- Coco, Simona
- Schüller, Ulrich
- Graf, Norbert
- Kim, Yoo-Jin
- Unterberg, Andreas
- Milde, Till
- Kulozik, Andreas E.
- Witt, Olaf
- Rössler, Jochen
- Ebinger, Martin
- Schuhmann, Martin U.
- Frühwald, Michael C.
- Hasselblatt, Martin
- Jabado, Nada
- Rutkowski, Stefan
- Clifford, Steven C.
- McCabe, Martin G.
- Wiemann, Stefan
- Brors, Benedikt
- Felsberg, Jörg
- Reifenberger, Guido
- Northcott, Paul A.
- Taylor, Michael D.
- Meyerson, Matthew
- Pomeroy, Scott L.
- Yaspo, Marie-Laure
- Korbel, Jan O.
- Korshunov, Andrey
- Eils, Roland
- Pfister, Stefan M.
- Lichter, Peter
- Venue
- Nature
- Published
- 2012-07-25
- Volume
- 488
- Issue
- 7409
- Pages
- 100-105
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3662966
- OpenAlex
- W2167532631
- Cited by
- 839
- References
- 27
- Citations by year
- 2026: 8 · 2025: 31 · 2024: 28 · 2023: 41 · 2022: 42 · 2021: 60 · 2020: 51 · 2019: 49 · 2018: 69 · 2017: 73 · 2016: 86 · 2015: 81 · 2014: 89 · 2013: 102 · 2012: 28
- FWCI
- 45.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- OPUS (Augsburg University) (submittedVersion, cc-by-nc-sa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Pediatric Brain Tumor Foundation
- Deutsches Krebsforschungszentrum
- Children's Cancer and Leukaemia Group
- Cancer Research UK (13457)
- Brain Tumour Charity (16/92, 10/106)
- Bundesministerium für Bildung und Forschung (01GS0883)
- Hungarian Scientific Research Fund
- Max-Planck-Gesellschaft
- Deutsche Krebshilfe (109252)
- Heidelberger Zentrum für Personalisierte Onkologie Deutsches Krebsforschungszentrum In Der Helmholtz-Gemeinschaft
- National Cancer Institute (R01CA109467)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- medulloblastoma, Group 3 medulloblastoma, Group 4 medulloblastoma, tetraploidy, somatic copy number alterations, TGF-beta signaling, NF-κB signaling, recurrent mutations, pediatric brain tumors, tumor heterogeneity
- MeSH terms
- Patched Receptors, Patched-1 Receptor, Aging, Amino Acid Sequence, Cell Transformation, Neoplastic, Cerebellar Neoplasms, Child, Chromatin, Chromosomes, Human, DNA Helicases, DNA-Binding Proteins, Humans, Medulloblastoma, Methylation, Mutation, Neoplasm Proteins, Nuclear Proteins, Phosphoprotein Phosphatases, Polyploidy, Receptors, Cell Surface, Transcription Factors, Signal Transduction, Oncogene Proteins, Fusion, Genome, Human, Sequence Analysis, RNA, T-Box Domain Proteins, Genomics, Wnt Proteins, beta Catenin, DEAD-box RNA Helicases, Hedgehog Proteins, Histone Demethylases, High-Throughput Nucleotide Sequencing, Mutation Rate
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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