Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes

  1. Yijun Ruan1,16,19
  1. 1Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore;
  2. 2Cancer Biology and Pharmacology, Genome Institute of Singapore, Singapore 138672, Singapore;
  3. 3Computational and Mathematical Biology, Genome Institute of Singapore, Singapore 138672, Singapore;
  4. 4Research Computing, Genome Institute of Singapore, Singapore 138672, Singapore;
  5. 5Department of Medicine, National University Health System, National University of Singapore, Singapore 119074, Singapore;
  6. 6Department of Surgery, National University Health System, National University of Singapore, Singapore 119074, Singapore;
  7. 7Department of Pathology, National University Health System, National University of Singapore, Singapore 119074, Singapore;
  8. 8Personal Genomics Solutions, Genome Institute of Singapore, Singapore 138672, Singapore;
  9. 9NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, Singapore 117456, Singapore
  10. 10Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore
  11. 11Infectious Disease, Genome Institute of Singapore, Singapore 138672, Singapore;
  12. 12Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
  13. 13Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
  14. 14Department of Oncology, Cancer Center Karolinska, Radiumhemmet, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden;
  15. 15Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
  16. 16Department of Biochemistry, National University of Singapore, Singapore 119074, Singapore;
  17. 17Duke-NUS Graduate Medical School, Singapore 169857, Singapore
    1. 18 These authors contributed equally to this work.

    Abstract

    Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA–PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers.

    Footnotes

    • 19 Corresponding author.

      E-mail ruanyj{at}gis.a-star.edu.sg; fax 65-6808-8304.

    • [Supplemental material is available for this article. The sequencing data from this study have been submitted to NCBI Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE26954.]

    • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.113555.110.

    • Received August 3, 2010.
    • Accepted February 8, 2011.

    Freely available online through the Genome Research Open Access option.

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