Article abstract
Nature Genetics 40, 722 - 729 (2008)
Published online: 27 April 2008 | doi:10.1038/ng.128
Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing
Peter J Campbell1,4, Philip J Stephens1,4, Erin D Pleasance1, Sarah O'Meara1, Heng Li1, Thomas Santarius1,3, Lucy A Stebbings1, Catherine Leroy1, Sarah Edkins1, Claire Hardy1, Jon W Teague1, Andrew Menzies1, Ian Goodhead1, Daniel J Turner1, Christopher M Clee1, Michael A Quail1, Antony Cox1, Clive Brown1, Richard Durbin1, Matthew E Hurles1, Paul A W Edwards2, Graham R Bignell1, Michael R Stratton1 & P Andrew Futreal1
Abstract
Human cancers often carry many somatically acquired genomic rearrangements, some of which may be implicated in cancer development. However, conventional strategies for characterizing rearrangements are laborious and low-throughput and have low sensitivity or poor resolution. We used massively parallel sequencing to generate sequence reads from both ends of short DNA fragments derived from the genomes of two individuals with lung cancer. By investigating read pairs that did not align correctly with respect to each other on the reference human genome, we characterized 306 germline structural variants and 103 somatic rearrangements to the base-pair level of resolution. The patterns of germline and somatic rearrangement were markedly different. Many somatic rearrangements were from amplicons, although rearrangements outside these regions, notably including tandem duplications, were also observed. Some somatic rearrangements led to abnormal transcripts, including two from internal tandem duplications and two fusion transcripts created by interchromosomal rearrangements. Germline variants were predominantly mediated by retrotransposition, often involving AluY and LINE elements. The results demonstrate the feasibility of systematic, genome-wide characterization of rearrangements in complex human cancer genomes, raising the prospect of a new harvest of genes associated with cancer using this strategy.
- Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
- Hutchison/Medical Research Council Research Centre and Department of Pathology, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
- Department of Neurosurgery, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK.
- These authors contributed equally to this work.
Correspondence to: Michael R Stratton1 e-mail: mrs@sanger.ac.uk
Correspondence to: P Andrew Futreal1 e-mail: paf@sanger.ac.uk
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