Signatures of mutation and selection in the cancer genome

Graham R. Bignell, Chris D. Greenman, Helen Davies, Adam P. Butler, Sarah Edkins, Jenny M. Andrews, Gemma Buck, Lina Chen, David Beare, Calli Latimer, Sara Widaa, Jonathon Hinton, Ciara Fahey, Beiyuan Fu, Sajani Swamy, Gillian L. Dalgliesh, Bin T. Teh, Panos Deloukas, Fengtang Yang, Peter J. Campbell, P. Andrew Futreal () and Michael R. Stratton ()
Additional contact information
Graham R. Bignell: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Chris D. Greenman: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Helen Davies: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Adam P. Butler: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Sarah Edkins: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Jenny M. Andrews: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Gemma Buck: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Lina Chen: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
David Beare: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Calli Latimer: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Sara Widaa: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Jonathon Hinton: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Ciara Fahey: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Beiyuan Fu: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Sajani Swamy: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Gillian L. Dalgliesh: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Bin T. Teh: Van Andel Institute, Grand Rapids, Michigan 49503, USA
Panos Deloukas: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Fengtang Yang: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Peter J. Campbell: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
P. Andrew Futreal: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Michael R. Stratton: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

Nature, 2010, vol. 463, issue 7283, 893-898

Abstract: Abstract The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.

Date: 2010
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DOI: 10.1038/nature08768

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