Patterns of somatic mutation in human cancer genomes

Christopher Greenman

Philip Stephens

Raffaella Smith

Gillian Dalgliesh

Adam Butler+57 authors

^{Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.}

^{EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.}

^{Molecular Pathology Unit, Neurosurgical Service and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.}

^{Royal Brompton Hospital, London SW3 6NP, UK.}

^{Ludwig Institute for Cancer Research, 1200 Brussels, Belgium.}

^{Laboratory of Pathology/Experimental Patho-Oncology, Erasmus MC University Medical Center Rotterdam, Daniel den Hoed Cancer Center, Josephine Nefkens Institute, 3000 DR Rotterdam, UCL 745, B-1200, The Netherlands.}

^{University of Pennsylvania Cancer Centre, Philadelphia, Pennsylvania 19104-6160, USA.}

^{Department of Gynaecological Oncology, Westmead Hospital and Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead NSW 2145, Australia.}

^{Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.}

^{Department of Haematology, Addenbrooke's NHS Trust and University of Cambridge, Cambridge CB2 0QQ, UK.}

^{Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge CB1 8RN, UK.}

^{Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Queensland 4029, Australia.}

^{Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.}

^{Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.}

Correspondence and requests for materials should be addressed to P.A.F. (ku.ca.regnas@fap) or M.R.S. (ku.ca.regnas@srm).

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.

Abstract

Cancers are clonal proliferations that arise owing to mutations that confer selective growth advantage on cells. The mutated genes that are causally implicated in cancer development are known as ‘cancer genes’ and more than 350 have thus far been identified (ref. 1 and http://www.sanger.ac.uk/genetics/CGP/Census/). Cancer genes have been identified by several different physical and genetic mapping strategies, by biological assays and as plausible biological candidates. Each of these approaches has identified a subset of cancer genes, leaving the possibility that others have been overlooked. The provision of the human genome sequence, therefore, led to the proposal that systematic resequencing of cancer genomes could reveal the full compendium of mutations in individual cancers and hence identify many of the remaining cancer genes2.

Somatic mutations occur in the genomes of all dividing cells, both normal and neoplastic. They may occur as a result of misincorporation during DNA replication or through exposure to exogenous or endogenous mutagens. Cancer genomes carry two biological classes of somatic mutation arising from these various processes. ‘Driver’ mutations confer growth advantage on the cell in which they occur, are causally implicated in cancer development and have therefore been positively selected. By definition, these mutations are in ‘cancer genes’. Conversely, ‘passenger’ mutations have not been subject to selection. They were present in the cell that was the progenitor of the final clonal expansion of the cancer, are biologically neutral and do not confer growth advantage. A challenge to all systematic mutation screens will, therefore, be to distinguish driver from passenger mutations. However, the prevalence and characteristics of driver and passenger mutations in cancer genomes are not currently well defined. The aim of these studies was to survey the numbers and patterns of somatic point mutations in a diverse set of human cancer genomes and hence to obtain insights into the relative contributions of driver and passenger mutations.

Footnotes

Supplementary Information is linked to the online version of the paper at www.nature.com/nature.

Reprints and permissions information is available at www.nature.com/reprints.

The authors declare no competing financial interests.

Footnotes

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