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.
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Funding for this research was provided by the Wellcome Trust. P.J.C. is a Kay Kendall Leukaemia Fund fellow, and T.S. has a fellowship from the Michael and Betty Kadoorie Cancer Genetics Research Programme. GlaxoSmithKline provided financial support for the SNP v6.0 microarray analysis for copy number.
Supplementary Tables 1, 4 and 5, Supplementary Figures 1 and 2 and Supplementary Note (ZIP 32617 kb)
Acquired and germline rearrangements identified in NCI-H2171. (XLS 281 kb)
Acquired and germline rearrangements identified in NCI-H1770. (XLS 73 kb)
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Campbell, P., Stephens, P., Pleasance, E. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 40, 722–729 (2008). https://doi.org/10.1038/ng.128
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