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Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations - Nature

  • ️Cho, Yoon-Jae
  • ️Sun Jul 22 2012

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Data deposits

Sequence data used for this analysis are available in dbGaP under accession phs000504.v1.p1.

References

  1. Central Brain Tumor Registry of the United States. Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2007http://www.cbtrus.org/2011-NPCR-SEER/WEB-0407-Report-3-3-2011.pdf (CBTRUS, 2011)

  2. Cho, Y.-J. et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J. Clin. Oncol. 29, 1424–1430 (2011)

    Article  PubMed  Google Scholar 

  3. Kool, M. et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS ONE 3, e3088 (2008)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  4. Remke, M. et al. Adult medulloblastoma comprises three major molecular variants. J. Clin. Oncol. 29, 2717–2723 (2011)

    Article  PubMed  Google Scholar 

  5. Taylor, M. D. e. t. a. l. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 123, 465–472 (2012)

    Article  CAS  PubMed  Google Scholar 

  6. Smoll, N. R. Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs). Cancer 118, 1313–1322 (2012)

    Article  PubMed  Google Scholar 

  7. Parsons, D. W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435–439 (2011)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Getz, G. et al. Comment on “The consensus coding sequences of human breast and colorectal cancers.”. Science 317, 1500 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Ming, J. E. et al. Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum. Genet. 110, 297–301 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, J. et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481, 329–334 (2012)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Grossmann, V. et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood 118, 6153–6163 (2011)

    Article  CAS  PubMed  Google Scholar 

  12. Oberoi, J. et al. Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery. Nature Struct. Mol. Biol. 18, 177–184 (2011)

    Article  CAS  Google Scholar 

  13. Baek, S. H. et al. Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway. Proc. Natl Acad. Sci. USA 100, 3245–3250 (2003)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wilson, B. G. & Roberts, C. W. M. SWI/SNF nucleosome remodellers and cancer. Nature Rev. Cancer 11, 481–492 (2011)

    Article  CAS  Google Scholar 

  15. Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004)

    Article  CAS  Google Scholar 

  16. Satow, R., Kurisaki, A., Chan, T.-c., Hamazaki, T. S. & Asashima, M. Dullard promotes degradation and dephosphorylation of BMP receptors and is required for neural induction. Dev. Cell 11, 763–774 (2006)

    Article  CAS  PubMed  Google Scholar 

  17. Peterson, T. R. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408–420 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Garbelli, A., Beermann, S., Di Cicco, G., Dietrich, U. & Maga, G. A motif unique to the human dead-box protein DDX3 is important for nucleic acid binding, ATP hydrolysis, RNA/DNA unwinding and HIV-1 replication. PLoS ONE 6, e19810 (2011)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Högbom, M. et al. Crystal structure of conserved domains 1 and 2 of the human DEAD-box helicase DDX3X in complex with the mononucleotide AMP. J. Mol. Biol. 372, 150–159 (2007)

    Article  PubMed  Google Scholar 

  20. Sengoku, T., Nureki, O., Nakamura, A., Kobayashi, S. & Yokoyama, S. Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa. Cell 125, 287–300 (2006)

    Article  CAS  PubMed  Google Scholar 

  21. Wang, L. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497–2506 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bentley, D. R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Genome Reference Consortium. Human Genome Overview http://www.ncbi.nlm.nih.gov/projects/genome/assembly/grc/human/ (2012)

  25. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ramos, A. et al. Oncotator http://www.broadinstitute.org/oncotator/ (2012)

  27. Robinson, J. T. et al. Integrative genomics viewer. Nature Biotechnol. 29, 24–26 (2011)

    Article  CAS  Google Scholar 

  28. Ren, J. et al. DOG 1.0: illustrator of protein domain structures. Cell Res. 19, 271–273 (2009)

    Article  CAS  PubMed  Google Scholar 

  29. Pettersen, E. F. et al. UCSF Chimera–a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants NHGRI U54HG003067 to E. S. Lander (E.S., D.A., S.B.G., G.G., M.M.); R01CA109467 (S.L.P., J.P.M.); R01CA105607 (H.G., T.M.R., M.M., S.L.P.); P30 HD18655 (S.L.P.); R01 CA030002 and CA050661 (T.M.R.); R01 NS046789 (G.R.C.); R01 CA154480 (P.T.); R25NS070682 (S.S.) and R01CA148699 (M.D.T.); St. Baldrick’s Foundation Scholar Award and the Beirne Faculty Scholar endowment and Center for Children’s Brain Tumors at Stanford University (Y.-J.C.); German Cancer Aid (109252) and the BMBF ICGC-PedBrain project (N.J., D.T.W.J., P.L., S.M.P.); HHMI (G.R.C.); the Pediatric Brain Tumor Foundation (M.D.T.); Canadian Institutes of Health Research Fellowship (T.J.P.); Restracomp funding from the Hospital for Sick Children (P.A.N.); and the Mullarkey Research Fund (S.L.P.). We thank Children’s Oncology Group and the Cooperative Human Tissue Network for providing tumour samples, the staff of the Broad Institute Biological Samples, Genome Sequencing and Genetic Analysis Platforms for their assistance in genomic processing of samples and generating the sequencing data used in this analysis, K. Keho and M. Brown at Pacific Biosciences for technical support with sample barcoding methods, and L. Gaffney of Broad Institute Communications for assistance with figure layout and design.

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Authors and Affiliations

  1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA ,

    Trevor J. Pugh, Daniel Auclair, James Bochicchio, Mauricio O. Carneiro, Scott L. Carter, Kristian Cibulskis, Rachel L. Erlich, Heidi Greulich, Michael S. Lawrence, Niall J. Lennon, Aaron McKenna, James Meldrim, Alex H. Ramos, Michael G. Ross, Carsten Russ, Erica Shefler, Andrey Sivachenko, Brian Sogoloff, Petar Stojanov, Pablo Tamayo, Jill P. Mesirov, Stacey B. Gabriel, Gad Getz, Matthew Meyerson, Scott L. Pomeroy & Yoon-Jae Cho

  2. Departments of Medical Oncology and of Biological Chemistry and Molecular Pharmacology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Trevor J. Pugh, Heidi Greulich, Alex H. Ramos, Thomas M. Roberts & Matthew Meyerson

  3. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Trevor J. Pugh, Shyamal Dilhan Weeraratne, Tenley C. Archer, Heidi Greulich, Alex H. Ramos, Vladimir Amani, Natalia Teider, Soma Sengupta, Jessica Pierre Francois, Thomas M. Roberts, Matthew Meyerson, Scott L. Pomeroy & Yoon-Jae Cho

  4. Department of Neurology, Children’s Hospital Boston, Boston, 02115, Massachusetts, USA

    Shyamal Dilhan Weeraratne, Tenley C. Archer, Vladimir Amani, Natalia Teider, Soma Sengupta, Jessica Pierre Francois, Scott L. Pomeroy & Yoon-Jae Cho

  5. Brandeis University, Waltham, 02453, Massachusetts, USA

    Daniel A. Pomeranz Krummel

  6. The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada ,

    Paul A. Northcott & Michael D. Taylor

  7. Departments of Neurology and Neurosurgery, Stanford University School of Medicine, Stanford, 94305, California, USA

    Furong Yu, Gerald R. Crabtree, Amanda G. Kautzman & Yoon-Jae Cho

  8. Howard Hughes Medical Institute at Stanford University, Stanford, 94305, California, USA

    Gerald R. Crabtree

  9. German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany ,

    Natalie Jäger, David T. W. Jones, Peter Lichter & Stefan M. Pfister

  10. Department of Pathology, Brigham and Women’s Hospital, Boston, 02115, Massachusetts, USA

    Matthew Meyerson

Authors

  1. Trevor J. Pugh

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  2. Shyamal Dilhan Weeraratne

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  3. Tenley C. Archer

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  4. Daniel A. Pomeranz Krummel

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  5. Daniel Auclair

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  6. James Bochicchio

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  7. Mauricio O. Carneiro

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  8. Scott L. Carter

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  9. Kristian Cibulskis

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  10. Rachel L. Erlich

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  11. Heidi Greulich

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  12. Michael S. Lawrence

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  13. Niall J. Lennon

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  14. Aaron McKenna

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  15. James Meldrim

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  16. Alex H. Ramos

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  17. Michael G. Ross

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  18. Carsten Russ

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  19. Erica Shefler

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  20. Andrey Sivachenko

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  21. Brian Sogoloff

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  22. Petar Stojanov

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  23. Pablo Tamayo

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  24. Jill P. Mesirov

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  25. Vladimir Amani

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  26. Natalia Teider

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  27. Soma Sengupta

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  28. Jessica Pierre Francois

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  29. Paul A. Northcott

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  30. Michael D. Taylor

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  31. Furong Yu

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  32. Gerald R. Crabtree

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  33. Amanda G. Kautzman

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  34. Stacey B. Gabriel

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  35. Gad Getz

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  36. Natalie Jäger

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  37. David T. W. Jones

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  38. Peter Lichter

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  39. Stefan M. Pfister

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  40. Thomas M. Roberts

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  41. Matthew Meyerson

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  42. Scott L. Pomeroy

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  43. Yoon-Jae Cho

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Contributions

Y.-J.C., M.M. and S.L.P. conceived the project. Y.-J.C., T.J.P., M.M. and S.L.P. wrote the manuscript with input from co-authors. S.D.W., T.C.A., J.P.F., S.S., N.T., Y.-J.C., A.G.K. and F.Y. performed functional characterization studies. D.A.P.K. generated in silico structural modelling of DDX3X mutations. T.J.P. conducted the bioinformatic analysis, supported by S.L.C., P.S., K.C., M.S.L., A.M., A.H.R., A.S., H.G., P.T., J.P.M., N.J. and D.T.W.J.; D.A., E.S., S.B.G., and G.G. facilitated transfer, sequencing and analysis of samples. P.A.N. and M.D.T. provided tissues for analysis. Y.-J.C., J.P.F. and V.A. processed tumour and blood samples for study. G.R.C. generated reagents used in functional characterization studies. P.L., S.M.P. and T.M.R. assisted with interpretation of results. J.B., M.O.C., R.L.E., N.J.L., J.M., M.G.R., C.R. and B.S. performed microfluidic PCR and single-molecule real-time sequencing for validation analysis.

Corresponding authors

Correspondence to Matthew Meyerson, Scott L. Pomeroy or Yoon-Jae Cho.

Ethics declarations

Competing interests

M.M. is a paid consultant for and equity holder in Foundation Medicine, a genomics-based oncology diagnostics company, and is a paid consultant for Novartis. Y.-J.C. has served on an advisory board for Novartis.

Supplementary information

Supplementary Information

This file contains Supplementary Text and additional references, Supplementary Figures 1-3 and Supplementary Table 5. (PDF 2067 kb)

Supplementary Data 1

This file contains Supplementary Table 1, showing the clinical, copy number and mutation data matrix. (XLSX 821 kb)

Supplementary Data 2

This file contains Supplementary Table 2 showing the list of candidate somatic mutations, Supplementary Table 4 showing the somatic mutations in histone methyltransferases and Supplementary Table 6, which shows the somatic mutations in RNA helicases. (XLSX 859 kb)

Supplementary Data 3

This file contains Supplementary Table 3, which shows MutSig hits for each medulloblastoma subtype considered independently. (XLSX 13091 kb)

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Pugh, T., Weeraratne, S., Archer, T. et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488, 106–110 (2012). https://doi.org/10.1038/nature11329

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  • Received: 03 February 2012

  • Accepted: 15 June 2012

  • Published: 22 July 2012

  • Issue Date: 02 August 2012

  • DOI: https://doi.org/10.1038/nature11329