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Diverse somatic mutation patterns and pathway alterations in human cancers

Abstract

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.

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Acknowledgements

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.

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Authors

Contributions

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.

Corresponding author

Correspondence to Somasekar Seshagiri.

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Competing interests

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://doi.org/10.1038/nature09208

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