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Clonal selection drives genetic divergence of metastatic medulloblastoma


Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord1. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system2. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour3,4. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

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Figure 1: Transposon mutagenesis models of disseminated human medulloblastoma.
Figure 2: Transposon-driven metastatic medulloblastoma genetically differs from the primary tumour.
Figure 3: Human medulloblastoma metastases are biologically distinct from their matched primary tumour.
Figure 4: Human medulloblastoma metastases are genetically distinct from their matched primary tumour.

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CpG methylation data have been deposited in the Gene Expression Omnibus under accession number GSE34356. Reprints and permissions information is available at


  1. Gajjar, A. et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 7, 813–820 (2006)

    Article  PubMed  Google Scholar 

  2. Mabbott, D. J. et al. Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. J. Clin. Oncol. 23, 2256–2263 (2005)

    Article  PubMed  Google Scholar 

  3. MacDonald, T. J. et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nature Genet. 29, 143–152 (2001)

    Article  CAS  PubMed  Google Scholar 

  4. Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 49–54 (2003)

    Article  CAS  PubMed  Google Scholar 

  5. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997)

    Article  CAS  PubMed  Google Scholar 

  6. Collier, L. S., Carlson, C. M., Ravimohan, S., Dupuy, A. J. & Largaespada, D. A. Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse. Nature 436, 272–276 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Dupuy, A. J., Akagi, K., Largaespada, D. A., Copeland, N. G. & Jenkins, N. A. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436, 221–226 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Helms, A. W., Abney, A. L., Ben-Arie, N., Zoghbi, H. Y. & Johnson, J. E. Autoregulation and multiple enhancers control Math1 expression in the developing nervous system. Development 127, 1185–1196 (2000)

    CAS  PubMed  Google Scholar 

  9. Wetmore, C., Eberhart, D. E. & Curran, T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 61, 513–516 (2001)

    CAS  PubMed  Google Scholar 

  10. Brett, B. T. et al. Novel molecular and computational methods improve the accuracy of insertion site analysis in Sleeping Beauty-induced tumors. PLoS ONE 6, e24668 (2011)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Northcott, P. A. et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nature Genet. 41, 465–472 (2009)

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  12. Forbes, S. A. et al. in Current Protocols in Human Genetics Ch. 10.11. 10.1002/0471142905.hg1011s57 (2008)

  13. Northcott, P. A. et al. Medulloblastoma comprises four distinct molecular variants. J. Clin. Oncol. 29, 1408–1414 (2011)

    Article  PubMed  Google Scholar 

  14. Nguyen, D. X. & Massague, J. Genetic determinants of cancer metastasis. Nature Rev. Genet. 8, 341–352 (2007)

    Article  CAS  PubMed  Google Scholar 

  15. Norton, L. & Massague, J. Is cancer a disease of self-seeding? Nature Med. 12, 875–878 (2006)

    Article  CAS  PubMed  Google Scholar 

  16. Luo, G., Ivics, Z., Izsvák, Z. & Bradley, A. Chromosomal transposition of a Tc1/mariner-like element in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 95, 10769–10773 (1998)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rao, G., Pedone, C. A., Coffin, C. M., Holland, E. C. & Fults, D. W. c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia 5, 198–204 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Swartling, F. J. et al. Pleiotropic role for MYCN in medulloblastoma. Genes Dev. 24, 1059–1072 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pfister, S. et al. Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J. Clin. Oncol. 27, 1627–1636 (2009)

    Article  PubMed  Google Scholar 

  20. Korshunov, A. et al. Accumulation of genomic aberrations during clinical progression of medulloblastoma. Acta Neuropathol. 116, 383–390 (2008)

    Article  CAS  PubMed  Google Scholar 

  21. Hahn, H. et al. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J. Biol. Chem. 275, 28341–28344 (2000)

    Article  CAS  PubMed  Google Scholar 

  22. Fidler, I. J. & Kripke, M. L. Metastasis results from preexisting variant cells within a malignant tumor. Science 197, 893–895 (1977)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Scheel, C., Onder, T., Karnoub, A. & Weinberg, R. A. Adaptation versus selection: the origins of metastatic behavior. Cancer Res. 67, 11476–11480 (2007)

    Article  CAS  PubMed  Google Scholar 

  24. Talmadge, J. E. Clonal selection of metastasis within the life history of a tumor. Cancer Res. 67, 11471–11475 (2007)

    Article  CAS  PubMed  Google Scholar 

  25. Talmadge, J. E. & Fidler, I. J. The biology of cancer metastasis: historical perspective. Cancer Res. 70, 5649–5669 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Geurts, A. M. et al. Gene transfer into genomes of human cells by the Sleeping Beauty transposon system. Mol. Ther. 8, 108–117 (2003)

    Article  CAS  PubMed  Google Scholar 

  27. Starr, T. K. et al. A transposon-based genetic screen in mice identifies genes altered in colorectal cancer. Science 323, 1747–1750 (2009)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gnekow, A. K. Recommendations of the brain tumor subcommittee for the reporting of trials. Med. Pediatr. Oncol. 24, 104–108 (1995)

    Article  CAS  PubMed  Google Scholar 

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M.D.T. holds a Canadian Institutes of Health Research Clinician-Scientist Phase II Award, was a Sontag Foundation Distinguished Scholar, and is supported by grants from the National Institutes of Health (R01CA148699), the Pediatric Brain Tumor Foundation, the Canadian Cancer Society, and Brainchild. X.W. was supported by a fellowship from the American Brain Tumor Association in tribute to Tracy Greenwood. L.G. was supported by a fellowship from the Davis M. Ferguson Fund from the American Brain Tumor Association. A.D. was supported by a Vanier Doctoral Fellowship from the Canadian Institutes of Health Research. L.S.C. was supported by a grant (K01CA122183) and a Kimmel Scholar award from the Kimmel Foundation. C.E. was supported by a grant from the National Institutes of Health (NS055089). We thank S. Archer for technical writing assistance.

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M.D.T., X.W., P.A.N., L.S.C., A.D. and D.L. conceived the research and planned the experiments. X.W., P.A.N., A.D., L.G. and D.J.H.S. carried out the vast majority of the experiments under M.D.T.’s guidance. C.E., T.V.M., D.Z., Y.-J.C., T.M., X.-N.L., V.P.C., M.G.M. and W.A.W. provided human tumour materials. All authors contributed experimental expertise and participated in the writing of the manuscript. A.J.D., D.J.H.S., T.E.S., S.W.S., K.A., J.K., A.L.S., D.L. and L.S.C. provided biostatistical and bioinformatic expertise. E.B. provided the clinical data and analysis. D.W.F. carried out the Akt experiments. N.J., J.S. and J.M. carried out the exome sequencing. H.W., S.M.P. and A.K. carried out the immunostaining of human medulloblastoma tissue microarrays and FISH for MYCN and MYC. S.C. carried out the pathological analysis of mouse brain tumours.

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Correspondence to Michael D. Taylor.

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The authors declare no competing financial interests.

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Wu, X., Northcott, P., Dubuc, A. et al. Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482, 529–533 (2012).

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