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Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing


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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Figure 1: Experimental protocol and outcome of sequencing.
Figure 2: Genome-wide acquired rearrangements.
Figure 3: Rearrangements in NCI-H2171.
Figure 4: Copy number.
Figure 5: Amplicons in NCI-H2171 and NCI-H1770.


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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.

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Authors and Affiliations



P.J.C. and P.J.S. equally contributed to generating and analysing sequencing, copy number, PCR and breakpoint data, and wrote the manuscript. E.D.P. coordinated the bioinformatic analyses with support for mapping from H.L. and A.C. and for pipelining from L.A.S., C.L., A.M. and J.W.T. S.O., S.E. and C.H. performed the confirmatory PCRs and Sanger sequencing. T.S. and P.A.W.E. performed FISH and SKY experiments. I.G. and M.A.Q. undertook library production from the cell lines, and C.M.C. and D.J.T. ran the massively parallel sequencing instruments. C.B., R.D. and M.E.H. contributed to the analysis and interpretation of data. G.R.B., M.R.S. and P.A.F. coordinated the research, interpreted the data and wrote the manuscript.

Corresponding authors

Correspondence to Michael R Stratton or P Andrew Futreal.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1, 4 and 5, Supplementary Figures 1 and 2 and Supplementary Note (ZIP 32617 kb)

Supplementary Table 2

Acquired and germline rearrangements identified in NCI-H2171. (XLS 281 kb)

Supplementary Table 3

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).

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