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Patterns of Somatic Mutation in Human Cancer Genomes

Christopher Greenman et al. Nature.

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.

Figures

Figure 1
Figure 1. The prevalence of somatic mutations in human cancer genomes
The number of somatic mutations (base substitutions, insertions/deletions and complex mutations) per Mb of DNA in 210 individual human cancers.
Figure 2
Figure 2. Mutation spectra of human cancers by tumour type
The numbers of each of the six classes of base substitution and insertion/deletions are shown. C:G>T:A substitutions have been divided into those at CpG dinucleotides and those not at CpG dinucleotides. The data for germline polymorphisms were generated from the protein kinase screen. The data from the two colorectal, two gastric and ovarian cancers that were mismatch-repair-deficient have been shown separately (MMR-deficient).
Figure 3
Figure 3. P-loop and activation segment mutations
ClustalW multi-sequence alignment of P-loop and activation segments with all positions of mis-sense mutations highlighted with underline/yellow. Positions of BRAF mutations are shown, with previously identified mutations highlighted in blue and mutations from the current study with underline/yellow. The gene name is indicated on the left. Mutations identified in the study are given to the right of the sequence.

Comment in

  • Cancer: drivers and passengers.
    Haber DA, Settleman J. Haber DA, et al. Nature. 2007 Mar 8;446(7132):145-6. doi: 10.1038/446145a. Nature. 2007. PMID: 17344839 No abstract available.

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