Clonal selection drives genetic divergence of metastatic medulloblastoma (original) (raw)

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References

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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Acknowledgements

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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Authors and Affiliations

1. Arthur and Sonia Labatt Brain Tumour Research Center, and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada,
   Xiaochong Wu, Paul A. Northcott, Adrian Dubuc, David J. H. Shih & Livia Garzia
2. Molecular & Cellular Biology Program, The University of Iowa, Iowa City, 52242, Iowa, USA
   Adam J. Dupuy & Todd E. Scheetz
3. and Department of Pediatric Oncology, German Cancer Research Center (DKFZ), Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany,
   Hendrik Witt & Stefan M. Pfister
4. Department of Laboratory Medicine and Pathobiology, University Health Network Pathology, Arthur and Sonia Labatt Brain Tumour Research Centre, University of Toronto, Toronto, Ontario M5S 1A1, Canada,
   Sidney Croul
5. Brain Tumour Program, Haematology and Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada,
   Eric Bouffet
6. Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, 84132, Utah, USA
   Daniel W. Fults
7. Johns Hopkins University, Baltimore, 21210, Maryland, USA
   Charles G. Eberhart
8. Virginia Commonwealth University, Richmond, 23284, Virginia, USA
   Timothy Van Meter
9. Department of Pathology and Neurosurgery, Division of Neuropathology, New York University School of Medicine, New York, 10016, New York, USA
   David Zagzag
10. Departments of Human Genetics and Experimental Medicine, McGill University, Montreal H3Z 2Z3, Quebec, Canada,
    Nada Jabado & Jacek Majewski
11. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 0G1, Canada,
    Jeremy Schwartzentruber
12. German Cancer Research Institute (DKFZ) and Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany,
    Andrey Korshunov
13. and Department of Pediatrics, Brain Tumor Program, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, 77030, Texas, USA
    Xiao-Nan Li
14. and McLaughlin Centre and Department of Molecular Genetics, Program in Genetics and Genomic Biology and The Centre for Applied Genomics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5S 1A1, Canada,
    Stephen W. Scherer
15. Departments of Neurology and Neurosurgery, Stanford University School of Medicine, Stanford, 94305, California, USA
    Yoon-Jae Cho
16. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, 43210, Ohio, USA
    Keiko Akagi
17. Pediatric Neuro-Oncology Program, Emory University School of Medicine, Atlanta, 30307, Georgia, USA
    Tobey J. MacDonald
18. Department of Human Genetics, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands,
    Jan Koster
19. School of Cancer and Enabling Sciences, University of Manchester, Manchester M20 4BX, UK,
    Martin G. McCabe
20. Masonic Cancer Center, University of Minnesota, Minneapolis, 55455, Minnesota, USA
    Aaron L. Sarver & David A. Largaespada
21. Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK,
    V. Peter Collins
22. Departments of Neurology, Pediatrics and Neurological Surgery, University of California, San Francisco, 94143, California, USA
    William A. Weiss
23. School of Pharmacology, University of Wisconsin, Madison, 53715, Wisconsin, USA
    Lara S. Collier
24. Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Center, and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada,
    Michael D. Taylor

Authors

1. Xiaochong Wu
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2. Paul A. Northcott
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3. Adrian Dubuc
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4. Adam J. Dupuy
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5. David J. H. Shih
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6. Hendrik Witt
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7. Sidney Croul
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8. Eric Bouffet
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9. Daniel W. Fults
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10. Charles G. Eberhart
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11. Livia Garzia
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12. Timothy Van Meter
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13. David Zagzag
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14. Nada Jabado
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15. Jeremy Schwartzentruber
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16. Jacek Majewski
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17. Todd E. Scheetz
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18. Stefan M. Pfister
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19. Andrey Korshunov
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20. Xiao-Nan Li
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21. Stephen W. Scherer
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22. Yoon-Jae Cho
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23. Keiko Akagi
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24. Tobey J. MacDonald
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25. Jan Koster
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26. Martin G. McCabe
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27. Aaron L. Sarver
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28. V. Peter Collins
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29. William A. Weiss
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30. David A. Largaespada
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31. Lara S. Collier
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32. Michael D. Taylor
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Contributions

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.

Corresponding author

Correspondence toMichael 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). https://doi.org/10.1038/nature10825

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• Received: 10 October 2010
• Accepted: 03 January 2012
• Published: 15 February 2012
• Issue Date: 23 February 2012
• DOI: https://doi.org/10.1038/nature10825