Article

Nature 455, 1061-1068 (23 October 2008) | doi:10.1038/nature07385; Received 28 July 2008; Accepted 1 September 2008; Published online 4 September 2008; Corrected 17 September 2008

There is a Corrigendum (28 February 2013) associated with this document.

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

The Cancer Genome Atlas Research Network

  1. Department of Pathology,
  2. Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
  3. Department of Neurosurgery,
  4. Department of Hematology and Medical Oncology,
  5. Winship Cancer Institute,
  6. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
  7. Department of Neurological Surgery,
  8. Department of Pathology, Henry Ford Hospital, Detroit, Michigan 48202, USA.
  9. Department of Pathology,
  10. Department of Neuro-Oncology,
  11. Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
  12. Department of Pathology,
  13. Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143, USA.
  14. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  15. Graduate Program in Structural and Computational Biology and Molecular Biophysics,
  16. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
  17. Department of Molecular Virology and Microbiology, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  18. The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
  19. Department of Biology, Institute of Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
  20. Department of Systems Biology, Harvard University, Boston, Massachusetts 02115, USA.
  21. The Genome Center at Washington University, Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
  22. Department of Medical Oncology,
  23. Center for Cancer Genome Discovery,
  24. Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
  25. Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  26. Harvard Medical School-Partners HealthCare Center for Genetics and Genomics, Boston, Massachusetts 02115, USA.
  27. Informatics Program,
  28. Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
  29. Center for Biomedical Informatics,
  30. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  31. USC Epigenome Center, University of Southern California, Los Angeles, California 90089, USA.
  32. Biometry and Clinical Trials Division,
  33. Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231, USA.
  34. Department of Molecular Biotechnology, Faculty of Bioscience and Engineering, Ghent University, Ghent B-9000, Belgium.
  35. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.
  36. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  37. Department of Genetics,
  38. Department of Urology, Stanford University School of Medicine, Stanford, California 94305, USA.
  39. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
  40. Department of Statistics,
  41. Department of Molecular and Cellular Biology, University of California at Berkeley, Berkeley, California 95720, USA.
  42. Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia.
  43. Department of Neurosurgery,
  44. Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
  45. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
  46. Department of Physiology and Biophysics, Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA.
  47. Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
  48. Department of Pathology, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
  49. Department of Genetics,
  50. Department of Pathology and Laboratory Medicine,
  51. Department of Internal Medicine, Division of Medical Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
  52. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
  53. International Genomics Consortium, Phoenix, Arizona 85004, USA.
  54. Computational Biology Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
  55. SRA International, Fairfax, Virginia 22033, USA.
  56. Center For Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, Maryland 20852, USA.
  57. Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
  58. National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  59. MLF Consulting, Arlington, Massachusetts 02474, USA.
  60. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  61. A list of participants and affiliations appears at the end of the paper.

Correspondence to: Correspondence and requests for materials should be addressed to L.C. (Email: lynda_chin@dfci.harvard.edu) or M.M. (Email: matthew_meyerson@dfci.harvard.edu).

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Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas—the most common type of adult brain cancer—and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

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