Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

    Article  CAS  Google Scholar 

  2. Mitelman, F., Johansson, B. & Mertens, F. Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nat. Genet. 36, 331–334 (2004).

    Article  CAS  Google Scholar 

  3. Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).

    Article  CAS  Google Scholar 

  4. Tomlins, S.A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007).

    Article  CAS  Google Scholar 

  5. Tomlins, S.A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  Google Scholar 

  6. Volik, S. et al. End-sequence profiling: sequence-based analysis of aberrant genomes. Proc. Natl. Acad. Sci. USA 100, 7696–7701 (2003).

    Article  Google Scholar 

  7. Bignell, G.R. et al. Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res. 17, 1296–1303 (2007).

    Article  CAS  Google Scholar 

  8. Howarth, K.D. et al. Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes. Oncogene advance online publication, doi: 10.1038/sj.onc.1210993 (17 December 2007).

  9. Gazdar, A.F. & Minna, J.D. NCI series of cell lines: an historical perspective. J. Cell. Biochem. 24(Suppl.), 1–11 (1996).

    Article  CAS  Google Scholar 

  10. Korbel, J.O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).

    Article  CAS  Google Scholar 

  11. Batzer, M.A. & Deininger, P.L. Alu repeats and human genomic diversity. Nat. Rev. Genet. 3, 370–379 (2002).

    Article  CAS  Google Scholar 

  12. Grigorova, M., Lyman, R.C., Caldas, C. & Edwards, P.A. Chromosome abnormalities in 10 lung cancer cell lines of the NCI-H series analyzed with spectral karyotyping. Cancer Genet. Cytogenet. 162, 1–9 (2005).

    Article  CAS  Google Scholar 

  13. Wu, G.J. et al. 17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes. Cancer Res. 60, 5371–5375 (2000).

    CAS  PubMed  Google Scholar 

  14. Venkatraman, E.S. & Olshen, A.B. A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics 23, 657–663 (2007).

    Article  CAS  Google Scholar 

  15. Cahill, D., Connor, B. & Carney, J.P. Mechanisms of eukaryotic DNA double strand break repair. Front. Biosci. 11, 1958–1976 (2006).

    Article  CAS  Google Scholar 

  16. Ruan, Y. et al. Fusion transcripts and transcribed retrotransposed loci discovered through comprehensive transcriptome analysis using paired-end diTags (PETs). Genome Res. 17, 828–838 (2007).

    Article  CAS  Google Scholar 

  17. Huppi, K. & Siwarski, D. Chimeric transcripts with an open reading frame are generated as a result of translocation to the Pvt-1 region in mouse B-cell tumors. Int. J. Cancer 59, 848–851 (1994).

    Article  CAS  Google Scholar 

  18. Cory, S., Graham, M., Webb, E., Corcoran, L. & Adams, J.M. Variant (6;15) translocations in murine plasmacytomas involve a chromosome 15 locus at least 72 kb from the c-myc oncogene. EMBO J. 4, 675–681 (1985).

    Article  CAS  Google Scholar 

  19. Basecke, J., Whelan, J.T., Griesinger, F. & Bertrand, F.E. The MLL partial tandem duplication in acute myeloid leukaemia. Br. J. Haematol. 135, 438–449 (2006).

    Article  Google Scholar 

  20. Dorrance, A.M. et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J. Clin. Invest. 116, 2707–2716 (2006).

    Article  CAS  Google Scholar 

  21. Robinson, K.O., Petersen, A.M., Morrison, S.N., Elso, C.M. & Stubbs, L. Two reciprocal translocations provide new clues to the high mutability of the Grid2 locus. Mamm. Genome 16, 32–40 (2005).

    Article  CAS  Google Scholar 

  22. Rozier, L., El-Achkar, E., Apiou, F. & Debatisse, M. Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer. Oncogene 23, 6872–6880 (2004).

    Article  CAS  Google Scholar 

  23. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  Google Scholar 

  24. Ning, Z., Cox, A.J. & Mullikin, J.C. SSAHA: a fast search method for large DNA databases. Genome Res. 11, 1725–1729 (2001).

    Article  CAS  Google Scholar 

Download references


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.

Author information

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing