Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations
Open accessAbstract
Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.
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Chromothripsis and BFB occur in many tumour types, and germline ATM and TP53 variants have been linked to such complex rearrangements in acute lymphoblastic leukaemia and medulloblastoma.
“Chromothripsis and BFB have been reported in numerous tumour types, and intriguingly, germline variants in ATM and TP53 were associated with such complex structural rearrangements in acute lymphoblastic leukaemia [26] and medulloblastoma [27].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [27]
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References 64 · Cited by 865
- Authors
- Rausch, T., Jones, D. T. W., Zapatka, M., Stütz, A. M., Zichner, T., Weischenfeldt, J., Jäger, N., Remke, M., Shih, D., Northcott, P. A., Pfaff, E., Tica, J., Wang, Q., Massimi, L., Witt, H., Bender, S., Pleier, S., Cin, H., Hawkins, C., Beck, C., von Deimling, A., Hans, V., Brors, B., Eils, R., Scheurlen, W., Blake, J., Benes, V., Kulozik, A. E., Witt, O., Martin, D., Zhang, C., Porat, R., Merino, D. M., Wasserman, J., Jabado, N., Fontebasso, A., Bullinger, L., Rücker, F. G., Döhner, K., Döhner, H., Koster, J., Molenaar, J. J., Versteeg, R., Kool, M., Tabori, U., Malkin, D., Korshunov, A., Taylor, M. D., Lichter, P., Pfister, S. M., & Korbel, J. O.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University of Toronto (CA)
- Evangelisches Krankenhaus Bielefeld (DE)
- Cnopf´sche Kinderklinik (DE)
- German Cancer Research Center (DE)
- McGill University Health Centre (CA)
- Universität Ulm (DE)
- Amsterdam University Medical Centers (NL)
- European Bioinformatics Institute (GB)
- Corresponding author
- Lichter, Peter
- Pfister, Stefan M.
- Korbel, Jan O.
- ORCID
- Rausch, Tobias
- Jones, David T.W.
- Zapatka, Marc
- Stütz, Adrian M.
- Zichner, Thomas
- Weischenfeldt, Joachim
- Jäger, Natalie
- Remke, Marc
- Shih, David
- Northcott, Paul A.
- Pfaff, Elke
- Tica, Jelena
- Wang, Qi
- Massimi, Luca
- Witt, Hendrik
- Hawkins, Cynthia
- Brors, Benedikt
- Eils, Roland
- Kulozik, Andreas E.
- Witt, Olaf
- Zhang, Cindy
- Merino, Diana M.
- Wasserman, Jonathan
- Jabado, Nada
- Bullinger, Lars
- Rücker, Frank G.
- Döhner, Konstanze
- Döhner, Hartmut
- Molenaar, Jan J.
- Versteeg, Rogier
- Kool, Marcel
- Tabori, Uri
- Malkin, David
- Korshunov, Andrey
- Taylor, Michael D.
- Lichter, Peter
- Pfister, Stefan M.
- Korbel, Jan O.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 148
- Issue
- 1-2
- Pages
- 59-71
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3332216
- OpenAlex
- W1969665013
- Cited by
- 865
- References
- 64
- Citations by year
- 2026: 20 · 2025: 31 · 2024: 44 · 2023: 53 · 2022: 50 · 2021: 63 · 2020: 57 · 2019: 57 · 2018: 77 · 2017: 68 · 2016: 63 · 2015: 70 · 2014: 77 · 2013: 76 · 2012: 58
- FWCI
- 29.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 563 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- Canadian Institutes of Health Research (MOP-97834)
- National Cancer Institute (R01CA148699, R01CA148699B)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- medulloblastoma, sonic hedgehog medulloblastoma, chromothripsis, TP53 mutation, germline TP53 mutation, Li-Fraumeni syndrome, complex chromosomal rearrangements, acute myeloid leukemia, p53, pediatric brain tumors
- MeSH terms
- Animals, Brain Neoplasms, Child, Chromosome Aberrations, Disease Models, Animal, DNA Mutational Analysis, Humans, Medulloblastoma, Middle Aged, Gene Rearrangement, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Li-Fraumeni Syndrome, Mice, DNA Copy Number Variations
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