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Patterns of somatic mutation in human cancer genomes

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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Figure 1: The prevalence of somatic mutations in human cancer genomes.
Figure 2: Mutation spectra of human cancers by tumour type.
Figure 3: P-loop and activation segment mutations.

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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.

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

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

Supplementary information

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 (PDF 2632 kb)

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Greenman, C., Stephens, P., Smith, R. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007). https://doi.org/10.1038/nature05610

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