• A Corrigendum to this article was published on 01 April 2007

This article has been updated

Abstract

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression1,2. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.

NOTE: In the version of this article initially published, the name of an author was spelled incorrectly as Laura MacConnaill. The correct spelling is Laura MacConaill. The error has been corrected in the HTML and PDF versions of the article.

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  • 14 March 2007

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Acknowledgements

We thank E. Lander and G. Getz for comments and advice. R.K.T. is a Mildred-Scheel fellow of the Deutsche Krebshilfe. R.K.T. is supported by the International Association for the Study of Lung Cancer (IASLC). R.M.D. is supported by the Swiss national science foundation (no: 3100A0-103671/1). A.G and J.M. are supported by the National Cancer Institute through SPORE grant P50CA70907. G.D.D. is supported by the Virginia and Daniel K. Ludwig Trust for Cancer Research, the Quick Family Fund for Cancer Research and the Ronald O. Perelman Fund for Cancer Research at Dana-Farber. I.K.M. and P.S.M. are supported by Accelerate Brain Tumor Cure. I.K.M., L.M.L, T.F.C., and P.S.M. are supported by the Henry E. Singleton Brain Tumor Program. I.K.M., L.M.L, T.F.C., S.F.N., M.M., W.R.S. and P.S.M. are supported by the Brain Tumor Funders' Collaborative. M.M. and L.A.G. are supported by a grant from Genentech, Inc. M.M. is supported by the American Cancer Society. L.A.G is supported by the National Cancer Institute, the Prostate Cancer Foundation, the Burroughs-Wellcome Fund, the Robert Wood Johnson Foundation and the Novartis Institute for Biomedical Research.

Author information

Author notes

    • Roman K Thomas
    • , Alissa C Baker
    •  & Ralph M DeBiasi

    These authors contributed equally to this work.

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.

    • Roman K Thomas
    • , Alissa C Baker
    • , Ralph M DeBiasi
    • , Wendy Winckler
    • , Thomas LaFramboise
    • , William M Lin
    • , Meng Wang
    • , Whei Feng
    • , Laura E MacConaill
    • , Jeffrey C Lee
    • , Rick Nicoletti
    • , Charlie Hatton
    • , Kwok-Kin Wong
    • , Rameen Beroukhim
    • , Jordi Barretina
    • , Amit Dutt
    • , Caroline Emery
    • , Heidi Greulich
    • , Kinjal Shah
    • , F Stephen Hodi
    • , Glenn Dranoff
    • , Massimo Loda
    • , Jonathan Fletcher
    • , Sabina Signoretti
    • , Kenneth C Anderson
    • , George D Demetri
    • , William R Sellers
    • , Matthew Meyerson
    •  & Levi A Garraway
  2. The Broad Institute of M.I.T. and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Roman K Thomas
    • , Ralph M DeBiasi
    • , Wendy Winckler
    • , Thomas LaFramboise
    • , William M Lin
    • , Meng Wang
    • , Whei Feng
    • , Laura E MacConaill
    • , Jeffrey C Lee
    • , Rick Nicoletti
    • , Charlie Hatton
    • , Mary Goyette
    • , Liuda Ziaugra
    • , Stacey Gabriel
    • , Rameen Beroukhim
    • , Jordi Barretina
    • , Amit Dutt
    • , Heidi Greulich
    • , Kinjal Shah
    • , Matthew Meyerson
    •  & Levi A Garraway
  3. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, Texas 75390-8593, USA.

    • Luc Girard
    • , Kuntal Majmudar
    • , Michael Peyton
    • , Adi Gazdar
    •  & John Minna
  4. Department of Surgery 2, Nagoya City University Medical School, Nagoya 467-8601, Japan.

    • Hidefumi Sasaki
  5. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

    • Adi Gazdar
  6. Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

    • John Minna
  7. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Scott A Armstrong
  8. Department of Molecular and Medical Pharmacology and Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles California 90095-1732, USA.

    • Ingo K Mellinghoff
  9. Department of Pathology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095-1732, USA.

    • Paul S Mischel
  10. Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095-1732, USA.

    • Tim F Cloughesy
  11. Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095-1732, USA.

    • Stan F Nelson
  12. Department of Neurosurgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095-1732, USA.

    • Linda M Liau
  13. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.

    • Kirsten Mertz
    • , Mark A Rubin
    • , Massimo Loda
    • , Jonathan Fletcher
    •  & Sabina Signoretti
  14. Institute of Surgical Pathology, University Hospital Zürich, 8091 Zürich, Switzerland.

    • Kirsten Mertz
    •  & Holger Moch
  15. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60637, USA.

    • William Catalona
  16. Genetics Branch, Center for Cancer Research, National Cancer Institute and National Naval Medical Center, Bethesda, Maryland, USA.

    • Frederic Kaye
  17. Ludwig Center for Cancer Research at Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • George D Demetri
  18. Department of Dermatology, University Hospital Zürich, 8091 Zürich, Switzerland.

    • Reinhard Dummer
  19. Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, and Center of Molecular Medicine, Austrian Academy of Sciences, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.

    • Stephan Wagner
  20. The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.

    • Meenhard Herlyn
  21. Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

    • William R Sellers
  22. Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

    • Matthew Meyerson
  23. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.

    • Matthew Meyerson
    •  & Levi A Garraway
  24. Melanoma Program in Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.

    • Levi A Garraway
  25. Max Planck Institute for Neurological Research with Klaus Joachim Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne, Gleueler Str. 50, 50931 Cologne, Germany.

    • Roman K Thomas
  26. Center for Integrated Oncology and Department I for Internal Medicine, University of Cologne, 50931 Cologne, Germany.

    • Roman K Thomas
    •  & Thomas Zander

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Levi A Garraway.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Distribution of peak height ratios for recurrent oncogene point mutations.

  2. 2.

    Supplementary Fig. 2

    Mutation prevalence as determined by high-throughput genotyping.

  3. 3.

    Supplementary Fig. 3

    Distribution of oncogene mutations by gene.

  4. 4.

    Supplementary Fig. 4

    Oncogene mutation prevalence by tumor type.

  5. 5.

    Supplementary Note

Excel files

  1. 1.

    Supplementary Table 1

    Oncogene mutations and nucleotide changes.

  2. 2.

    Supplementary Table 2

    Oncogene mutation peak height ratios.

  3. 3.

    Supplementary Table 3

    Oncogene mutation assay completion.

About this article

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DOI

https://doi.org/10.1038/ng1975

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