Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations (original) (raw)

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Data deposits

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

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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 toMatthew Meyerson, Scott L. Pomeroy or Yoon-Jae Cho.

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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