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All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.
The genomes of all cancer cells carry somatic mutations1. These may include base substitutions, small insertions and deletions (indels), rearrangements and copy number alterations together with epigenetic changes. Some of these somatic alterations, known as driver mutations, confer selective clonal growth advantage and are causally implicated in oncogenesis. By definition, these are found in cancer genes. The remainder are passengers which do not contribute to cancer development. However, passenger mutations bear the imprints of the mutational mechanisms that have generated them, unsullied by processes of selection, and thus provide insights into the aetiology and pathogenesis of cancer.
Over the last quarter of a century several strategies have been used to detect the various classes of somatic mutation in cancer genomes1. As a result, approximately 400 cancer genes have been identified1,2 (http://www.sanger.ac.uk/genetics/CGP/Census/) and somatic mutations from thousands of tumours have provided insights into the mutational processes operative in human cancer1,3.
With the advent of the human genome sequence a new strategy was proposed1,4. Systematic sequencing would identify all somatic mutations of all classes in individual cancer genomes, yielding complete catalogues of somatic mutation. Technological limitations initially constrained this to polymerase chain reaction (PCR)-based resequencing of the coding exons of protein-coding genes in order to find base substitutions and small indels5-10. Recently, however, several novel technologies have been developed11,12. These allow sequencing of randomly generatedDNAfragments...