Diverse somatic mutation patterns and pathway alterations in human cancers


The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics1. Here we report the identification of 2,576 somatic mutations across 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for gα subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Gα subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.

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Figure 1: Diverse patterns of significantly mutated genes across cancer subtypes.
Figure 2: GRM and BAI are frequently mutated gene families.
Figure 3: Integrated analysis of somatic mutations and copy number alterations.
Figure 4: Integrated analysis of signalling pathways reveals a role for MAP2K4 mutations in cancer.

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Primary accessions

Gene Expression Omnibus

Protein Data Bank

Data deposits

The CGH microarray data has been submitted to the GEO database under the accession number GSE20393.


  1. 1

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

  2. 2

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

  3. 3

    Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007)

  4. 4

    Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007)

  5. 5

    The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008)

  6. 6

    Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008)

  7. 7

    Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008)

  8. 8

    Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008)

  9. 9

    Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010)

  10. 10

    Peters, B. A. et al. Highly efficient somatic-mutation identification using Escherichia coli mismatch-repair detection. Nature Methods 4, 713–715 (2007)

  11. 11

    Zheng, J. et al. High-throughput, high-accuracy array-based resequencing. Proc. Natl Acad. Sci. USA 106, 6712–6717 (2009)

  12. 12

    Fakhrai-Rad, H. et al. SNP discovery in pooled samples with mismatch repair detection. Genome Res. 14, 1404–1412 (2004)

  13. 13

    Forbes, S. A. et al. The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr. Protoc. Hum. Genet. 10.11 10.1002/0471142905.hg1011s57 (2008)

  14. 14

    Tomlins, S. A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007)

  15. 15

    Parmigiani, G. et al. Design and analysis issues in genome-wide somatic mutation studies of cancer. Genomics 93, 17–21 (2009)

  16. 16

    Rubin, A. F. & Green, P. Comment on “The consensus coding sequences of human breast and colorectal cancers”. Science 317, 1500c (2007)

  17. 17

    Pollock, P. M. et al. Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nature Genet. 34, 108–112 (2003)

  18. 18

    Shiratsuchi, T., Nishimori, H., Ichise, H., Nakamura, Y. & Tokino, T. Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). Cytogenet. Cell Genet. 79, 103–108 (1997)

  19. 19

    Weinstein, L. S. & Shenker, A. G protein mutations in human disease. Clin. Biochem. 26, 333–338 (1993)

  20. 20

    Bastida Eizaguirre, M., Iturbe Ortiz De Urbina, R., Arto Urzainqui, M., Ezquerra Larreina, R. & Escalada San Martin, J. Albright hereditary osteodystrophy: identification of a novel mutation in a family. An. Esp. Pediatr. 54, 598–600 (2001)

  21. 21

    Ram, P. T., Horvath, C. M. & Iyengar, R. Stat3-mediated transformation of NIH-3T3 cells by the constitutively active Q205L Gαo protein. Science 287, 142–144 (2000)

  22. 22

    Van Raamsdonk, C. D. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599–602 (2009)

  23. 23

    Whitmarsh, A. J. & Davis, R. J. Role of mitogen-activated protein kinase kinase 4 in cancer. Oncogene 26, 3172–3184 (2007)

  24. 24

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

  25. 25

    Parsons, D. W. et al. Colorectal cancer: mutations in a signalling pathway. Nature 436, 792 (2005)

  26. 26

    Cazillis, M. et al. Disruption of MKK4 signaling reveals its tumor-suppressor role in embryonic stem cells. Oncogene 23, 4735–4744 (2004)

  27. 27

    Jaiswal, B. S. et al. Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463–474 (2009)

  28. 28

    Burgess, A. W. et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12, 541–552 (2003)

  29. 29

    Franklin, M. C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5, 317–328 (2004)

  30. 30

    Stephens, P. et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525–526 (2004)

  31. 31

    Kidd, K. K. et al. Developing a SNP panel for forensic identification of individuals. Forensic Sci. Int. 164, 20–32 (2006)

  32. 32

    Sanchez, J. J. et al. A multiplex assay with 52 single nucleotide polymorphisms for human identification. Electrophoresis 27, 1713–1724 (2006)

  33. 33

    Jerome Marson, V. et al. Expression of TTF-1 and cytokeratins in primary and secondary epithelial lung tumours: correlation with histological type and grade. Histopathology 45, 125–134 (2004)

  34. 34

    Hupe, P., Stransky, N., Thiery, J. P., Radvanyi, F. & Barillot, E. Analysis of array CGH data: from signal ratio to gain and loss of DNA regions. Bioinformatics 20, 3413–3422 (2004)

  35. 35

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

  36. 36

    Ng, P. C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001)

  37. 37

    Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002)

  38. 38

    Kaminker, J. S., Zhang, Y., Watanabe, C. & Zhang, Z. CanPredict: a computational tool for predicting cancer-associated missense mutations. Nucleic Acids Res. 35 W595–W598 10.1093/nar/gkm405 (2007)

  39. 39

    Kaminker, J. S. et al. Distinguishing cancer-associated missense mutations from common polymorphisms. Cancer Res. 67, 465–473 (2007)

  40. 40

    Yue, P. et al. Inferring the functional effects of mutation through clusters of homologus proteins. Hum. Mutat. 31, 264–271 (2009)

  41. 41

    Clifford, R. J., Edmonson, M. N., Nguyen, C. & Buetow, K. H. Large-scale analysis of non-synonymous coding region single nucleotide polymorphisms. Bioinformatics 20, 1006–1014 (2004)

  42. 42

    Bairoch, A., Boeckmann, B., Ferro, S. & Gasteiger, E. Swiss-Prot: juggling between evolution and stability. Brief. Bioinform. 5, 39–55 (2004)

  43. 43

    Finn, R. D. et al. Pfam: clans, web tools and services. Nucleic Acids Res. 34, D247–D251 (2006)

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We acknowledge Genentech DNA Sequencing, Oligo and Microarray, and FACS labs for their help with the project. We thank the Genentech Bioinformatics group for informatics infrastructure support and the Pathology Core Labs for providing histology, immunohistochemistry and tissue management support. We also thank U. Vitt and W. Forrest for their help during the course of this project, and L. Phillips and D. Shames for their help with preparation of this manuscript.

Author information

Bioinformatics analysis: Z.K., P.Y., P.M.H., R.B., B.A.P., M.M., V.E.H.C., J.S.K., L.L., Z.Z., D.S. and S.S. MRD planning and sorting: J.Z. and M.F. Mutation validation: Z.K., J.S., D.B., W.Y., L.P.T., S.C.S. and K.P. CGH, sequencing and microarray studies: Z.M. and P.M.H. Biological studies: B.S.J., V.J., S.Ch., S.Co., D.P.D., D.S. and S.S. Structural predictions: W.W. and C.E. Pathology support: H.M.S., D.A.E. and P.W. Project conception, scientific oversight and input: F.J.d.S. and S.S. Manuscript preparation: Z.K. and S.S.

Correspondence to Somasekar Seshagiri.

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Most of the authors are either employees of Genentech Inc. or Affymetrix Inc.

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Kan, Z., Jaiswal, B., Stinson, J. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010). https://xs.scihub.ltd/https://doi.org/10.1038/nature09208

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