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Abstract

Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be ‘passengers’ that do not contribute to oncogenesis. However, there was evidence for ‘driver’ mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.

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References

  1. 1.

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

  2. 2.

    et al. Cancer and genomics. Nature 409, 850–852 (2001)

  3. 3.

    Targeted cancer therapy. Nature 432, 294–297 (2004)

  4. 4.

    , , , & The protein kinase complement of the human genome. Science 298, 1912–1934 (2002)

  5. 5.

    et al. A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nature Genet. 37, 590–592 (2005)

  6. 6.

    et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 65, 7591–7595 (2005)

  7. 7.

    et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66, 3987–3991 (2006)

  8. 8.

    et al. Sequence analysis of the protein kinase gene family in human testicular germ-cell tumours of adolescents and adults. Genes Chromosom. Cancer 45, 42–46 (2006)

  9. 9.

    et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949 (2003)

  10. 10.

    et al. Prevalence of somatic alterations in the colorectal cancer cell genome. Proc. Natl Acad. Sci. USA 99, 3076–3080 (2002)

  11. 11.

    , & Adjuvant chemotherapy in the treatment of high grade gliomas. Cancer Treat. Rev. 31, 79–89 (2005)

  12. 12.

    , & Human mismatch repair, drug-induced DNA damage, and secondary cancer. Biochimie 85, 1149–1160 (2003)

  13. 13.

    , , , & Statistical analysis of pathogenicity of somatic mutations in cancer. Genetics 173, 2187–2198 (2006)

  14. 14.

    , & Likelihood models of somatic mutation and codon substitution in cancer genes. Genetics 165, 695–705 (2003)

  15. 15.

    & A codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol. Biol. Evol. 11, 725–736 (1994)

  16. 16.

    et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659–3662 (2002)

  17. 17.

    et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)

  18. 18.

    & Titin and its associated proteins: the third myofilament system of the sarcomere. Adv. Protein Chem. 71, 89–119 (2005)

  19. 19.

    & D-Titin: a giant protein with dual roles in chromosomes and muscles. J. Cell Biol. 151, 639–652 (2000)

  20. 20.

    , & Human autoantibodies reveal Titin as a chromosomal protein. J. Cell Biol. 141, 321–333 (1998)

  21. 21.

    , , & Nuclear Titin interacts with A- and B-type lamins in vitro and in vivo. J. Cell Sci. 119, 239–249 (2006)

  22. 22.

    ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003)

  23. 23.

    et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nature Genet. 38, 873–875 (2006)

  24. 24.

    et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995)

  25. 25.

    et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nature Genet. 28, 184–187 (2001)

  26. 26.

    et al. Mechanism of activation of the RAF–ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004)

  27. 27.

    et al. Definition of an inhibitory juxtamembrane WW-like domain in the platelet-derived growth factor beta receptor. J. Biol. Chem. 277, 38627–38634 (2002)

  28. 28.

    et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res. 57, 4177–4182 (1997)

  29. 29.

    et al. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res. 58, 2339–2342 (1998)

  30. 30.

    et al. Colorectal cancer Mutations in a signalling pathway. Nature 436, 792 (2005)

  31. 31.

    , , , & Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. Biochim. Biophys. Acta 1697, 89–101 (2004)

  32. 32.

    & Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807–869 (2001)

  33. 33.

    et al. Reactome: a knowledgebase of biological pathways. Nucleic Acids Res. 33, D428–D432 (2005)

  34. 34.

    et al. The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids Res. 33, D284–D288 (2005)

  35. 35.

    , & Event ontology: a pathway-centric ontology for biological processes. Pac. Symp. Biocomput. 11, 152–163 (2006)

  36. 36.

    , , , & FGFs, their receptors, and human limb malformations: clinical and molecular correlations. Am. J. Med. Genet. 112, 266–278 (2002)

  37. 37.

    et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nature Genet. 23, 18–20 (1999)

  38. 38.

    et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006)

  39. 39.

    et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997–7000 (2002)

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Acknowledgements

We would like to thank J. Leary and the ABN-Oncology group (funded by the National Health and Medical Research Council of Australia), the Hauenstein Foundation and the Cooperative Human Tissue Network for providing samples for analysis, G. Wu and L. Stein for the development of the joint Reactome, Panther, INOH database, and C. Marshall and N. Rahman for comments. The studies were funded by the NIH and the Wellcome Trust.

Author information

Affiliations

  1. Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK

    • Christopher Greenman
    • , Philip Stephens
    • , Raffaella Smith
    • , Gillian L. Dalgliesh
    • , Christopher Hunter
    • , Graham Bignell
    • , Helen Davies
    • , Jon Teague
    • , Adam Butler
    • , Claire Stevens
    • , Sarah Edkins
    • , Sarah O’Meara
    • , Tim Avis
    • , Syd Barthorpe
    • , Gurpreet Bhamra
    • , Gemma Buck
    • , Bhudipa Choudhury
    • , Jody Clements
    • , Jennifer Cole
    • , Ed Dicks
    • , Simon Forbes
    • , Kris Gray
    • , Kelly Halliday
    • , Rachel Harrison
    • , Katy Hills
    • , Jon Hinton
    • , Andy Jenkinson
    • , David Jones
    • , Andy Menzies
    • , Tatiana Mironenko
    • , Janet Perry
    • , Keiran Raine
    • , Dave Richardson
    • , Rebecca Shepherd
    • , Alexandra Small
    • , Calli Tofts
    • , Jennifer Varian
    • , Tony Webb
    • , Sofie West
    • , Sara Widaa
    • , Andy Yates
    • , Peter Campbell
    • , Richard Wooster
    • , P. Andrew Futreal
    •  & Michael R. Stratton
  2. EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK

    • Imre Vastrik
    • , Esther E. Schmidt
    •  & Ewan Birney
  3. Molecular Pathology Unit, Neurosurgical Service and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA

    • Daniel P. Cahill
    •  & David N. Louis
  4. Royal Brompton Hospital, London SW3 6NP, UK

    • Peter Goldstraw
    •  & Andrew G. Nicholson
  5. Ludwig Institute for Cancer Research, 1200 Brussels, Belgium

    • Francis Brasseur
  6. Laboratory of Pathology/Experimental Patho-Oncology, Erasmus MC University Medical Center Rotterdam, Daniel den Hoed Cancer Center, Josephine Nefkens Institute, 3000 DR Rotterdam, UCL 745, B-1200, The Netherlands

    • Leendert Looijenga
  7. University of Pennsylvania Cancer Centre, Philadelphia, Pennsylvania 19104-6160, USA

    • Barbara L. Weber
  8. Department of Gynaecological Oncology, Westmead Hospital and Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead NSW 2145, Australia

    • Yoke-Eng Chiew
    •  & Anna deFazio
  9. Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK

    • Mel F. Greaves
    •  & Michael R. Stratton
  10. Department of Haematology, Addenbrooke’s NHS Trust and University of Cambridge, Cambridge CB2 0QQ, UK

    • Anthony R. Green
  11. Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge CB1 8RN, UK

    • Douglas F. Easton
  12. Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Queensland 4029, Australia

    • Georgia Chenevix-Trench
  13. Van Andel Research Institute, Grand Rapids, Michigan 49503, USA

    • Min-Han Tan
    • , Sok Kean Khoo
    •  & Bin Tean Teh
  14. Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong

    • Siu Tsan Yuen
    •  & Suet Yi Leung

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Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding authors

Correspondence to P. Andrew Futreal or Michael R. Stratton.

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains Supplementary Methods and Supplementary Tables 1-5 with Legends and Supplementary Figure 1. The Supplementary Tables show protein kinase genes in the screen (Table 1); somatic mutations indentified (Table 2); cancer samples analysed (Table 3); germline variants identified (Table 4) and kinase gene ranking by probability of carrying driver mutations (Table 5). The Supplementary Figure 1 illustrates mutation prevalence in individual cancers across cancer types

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DOI

https://doi.org/10.1038/nature05610

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