Skip to main content

Advertisement

SpringerLink
Log in

The power of NGS technologies to delineate the genome organization in cancer: from mutations to structural variations and epigenetic alterations

  • NON-THEMATIC REVIEW
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The development of cancer is characterized by the joined occurrence of alterations on different levels—from single nucleotide changes via structural and copy number variations to epigenetic alterations. With the advent of advanced technologies such as next generation sequencing, we have now the tools in hands to put some light on complex processes and recognize systematic patterns that develop throughout cancer progression. The combination of single hypothesis-driven experiments with a system-wide genetic view enables us to prove so far not addressable questions such as the influence of DNA methylation on gene expression or the disruption of genome homeostasis by structural variations and miRNA expression patterns. Out of this enormous amount of information, specific biomarkers for cancer progression have been discovered, which pave the way for the development of new therapeutic strategies. Here, we will review the status quo of integrative cancer genomic approaches, give an overview over the power of next generation sequencing technologies in oncology, and outline future perspective. Both sides—clinical as well as basic research aspects—will be considered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Krawitz, P. M., Schweiger, M. R., Rodelsperger, C., Marcelis, C., Kolsch, U., et al. (2010). Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nature Genetics, 42, 827–829.

    Article  PubMed  CAS  Google Scholar 

  2. Ng, S. B., Turner, E. H., Robertson, P. D., Flygare, S. D., Bigham, A. W., et al. (2009). Targeted capture and massively parallel sequencing of 12 human exomes. Nature, 461, 272–276.

    Article  PubMed  CAS  Google Scholar 

  3. Bagnyukova, T., Serebriiskii, I. G., Zhou, Y., Hopper-Borge, E. A., Golemis, E. A., et al. (2010). Chemotherapy and signaling: how can targeted therapies supercharge cytotoxic agents? Cancer Biol Ther, 10(9), 839–853.

    Article  PubMed  CAS  Google Scholar 

  4. Branton, D., Deamer, D. W., Marziali, A., Bayley, H., Benner, S. A., et al. (2008). The potential and challenges of nanopore sequencing. Nature Biotechnology, 26, 1146–1153.

    Article  PubMed  CAS  Google Scholar 

  5. Pleasance, E. D., Stephens, P. J., O’Meara, S., McBride, D. J., Meynert, A., et al. (2010). A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature, 463, 184–190.

    Article  PubMed  CAS  Google Scholar 

  6. Pleasance, E. D., Cheetham, R. K., Stephens, P. J., McBride, D. J., Humphray, S. J., et al. (2010). A comprehensive catalogue of somatic mutations from a human cancer genome. Nature, 463, 191–196.

    Article  PubMed  CAS  Google Scholar 

  7. Ley, T. J., Mardis, E. R., Ding, L., Fulton, B., McLellan, M. D., et al. (2008). DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature, 456, 66–72.

    Article  PubMed  CAS  Google Scholar 

  8. Shah, S. P., Morin, R. D., Khattra, J., Prentice, L., Pugh, T., et al. (2009). Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature, 461, 809–813.

    Article  PubMed  CAS  Google Scholar 

  9. Gilbert, M. T., Haselkorn, T., Bunce, M., Sanchez, J. J., Lucas, S. B., et al. (2007). The isolation of nucleic acids from fixed, paraffin-embedded tissues-which methods are useful when? PLoS ONE, 2, e537.

    Article  PubMed  Google Scholar 

  10. Schweiger, M. R., Kerick, M., Timmermann, B., Albrecht, M. W., Borodina, T., et al. (2009). Genome-wide massively parallel sequencing of formaldehyde fixed-paraffin embedded (FFPE) tumor tissues for copy-number- and mutation-analysis. PLoS ONE, 4, e5548.

    Article  PubMed  Google Scholar 

  11. Bian, Y. S., Yan, P., Osterheld, M. C., Fontolliet, C., & Benhattar, J. (2001). Promoter methylation analysis on microdissected paraffin-embedded tissues using bisulfite treatment and PCR-SSCP. Biotechniques, 30, 66–72.

    PubMed  CAS  Google Scholar 

  12. Chiu, R. W., Chan, K. C., Gao, Y., Lau, V. Y., Zheng, W., et al. (2008). Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proceedings of the National Academy of Sciences of the United States of America, 105, 20458–20463.

    Article  PubMed  CAS  Google Scholar 

  13. Kerjean, A., Vieillefond, A., Thiounn, N., Sibony, M., Jeanpierre, M., et al. (2001). Bisulfite genomic sequencing of microdissected cells. Nucleic Acids Research, 29, E106–106.

    Article  PubMed  CAS  Google Scholar 

  14. Fan, H. C., Blumenfeld, Y. J., Chitkara, U., Hudgins, L., & Quake, S. R. (2008). Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proceedings of the National Academy of Sciences of the United States of America, 105, 16266–16271.

    Article  PubMed  CAS  Google Scholar 

  15. van der Vaart, M., Semenov, D. V., Kuligina, E. V., Richter, V. A., & Pretorius, P. J. (2009). Characterisation of circulating DNA by parallel tagged sequencing on the 454 platform. Clinica Chimica Acta, 409, 21–27.

    Article  Google Scholar 

  16. Beck, J., Urnovitz, H. B., Mitchell, W. M., & Schutz, E. (2010). Next generation sequencing of serum circulating nucleic acids from patients with invasive ductal breast cancer reveals differences to healthy and nonmalignant controls. Molecular Cancer Research, 8, 335–342.

    Article  PubMed  CAS  Google Scholar 

  17. McBride, D. J., Orpana, A. K., Sotiriou, C., Joensuu, H., Stephens, P. J., et al. (2010). Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Genes, Chromosomes & Cancer, 49, 1062–1069.

    Article  CAS  Google Scholar 

  18. Maxam, A. M., & Gilbert, W. (1977). A new method for sequencing DNA. Proceedings of the National Academy of Sciences of the United States of America, 74, 560–564.

    Article  PubMed  CAS  Google Scholar 

  19. Sanger, F., Nicklen, S., & Coulson, A. R. (1977). DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 74, 5463–5467.

    Article  PubMed  CAS  Google Scholar 

  20. The International Human Genome Sequencing Consortium (2004). Finishing the euchromatic sequence of the human genome. Nature, 431, 931–945.

    Article  Google Scholar 

  21. Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., et al. (2001). Initial sequencing and analysis of the human genome. Nature, 409, 860–921.

    Article  PubMed  CAS  Google Scholar 

  22. Mardis, E. R. (2008). Next-generation DNA sequencing methods. Annual Review of Genomics and Human Genetics, 9, 387–402.

    Article  PubMed  CAS  Google Scholar 

  23. Shendure, J., & Ji, H. (2008). Next-generation DNA sequencing. Nature Biotechnology, 26, 1135–1145.

    Article  PubMed  CAS  Google Scholar 

  24. Metzker, M. L. (2010). Sequencing technologies—the next generation. Nature Reviews. Genetics, 11, 31–46.

    Article  PubMed  CAS  Google Scholar 

  25. Ding, L., Wendl, M. C., Koboldt, D. C., & Mardis, E. R. (2010). Analysis of next-generation genomic data in cancer: accomplishments and challenges. Human Molecular Genetics, 19, R188–R196.

    Article  PubMed  CAS  Google Scholar 

  26. Meyerson, M., Gabriel, S., & Getz, G. (2010). Advances in understanding cancer genomes through second-generation sequencing. Nature Reviews. Genetics, 11, 685–696.

    Article  PubMed  CAS  Google Scholar 

  27. Rothberg, J. M., & Leamon, J. H. (2008). The development and impact of 454 sequencing. Nature Biotechnology, 26, 1117–1124.

    Article  PubMed  CAS  Google Scholar 

  28. Margulies, M., Egholm, M., Altman, W. E., Attiya, S., Bader, J. S., et al. (2005). Genome sequencing in microfabricated high-density picolitre reactors. Nature, 437, 376–380.

    PubMed  CAS  Google Scholar 

  29. Ronaghi, M. (2001). Pyrosequencing sheds light on DNA sequencing. Genome Research, 11, 3–11.

    Article  PubMed  CAS  Google Scholar 

  30. Bentley, D. R., Balasubramanian, S., Swerdlow, H. P., Smith, G. P., Milton, J., et al. (2008). Accurate whole human genome sequencing using reversible terminator chemistry. Nature, 456, 53–59.

    Article  PubMed  CAS  Google Scholar 

  31. Shendure, J., Porreca, G. J., Reppas, N. B., Lin, X., McCutcheon, J. P., et al. (2005). Accurate multiplex polony sequencing of an evolved bacterial genome. Science, 309, 1728–1732.

    Article  PubMed  CAS  Google Scholar 

  32. Blow, N. (2008). DNA sequencing: generation next-next. Nat Methods, 5(6), 267–274.

    Article  CAS  Google Scholar 

  33. Clarke, J., Wu, H. C., Jayasinghe, L., Patel, A., Reid, S., et al. (2009). Continuous base identification for single-molecule nanopore DNA sequencing. Nature Nanotechnology, 4, 265–270.

    Article  PubMed  CAS  Google Scholar 

  34. Greenleaf, W. J., & Block, S. M. (2006). Single-molecule, motion-based DNA sequencing using RNA polymerase. Science, 313, 801.

    Article  PubMed  CAS  Google Scholar 

  35. Sugiyama, S. (2006). Application of scanning probe microscopy to genetic analysis. Japanese journal of applied physics, 45, 4.

    Article  Google Scholar 

  36. Pourmand, N., Karhanek, M., Persson, H. H., Webb, C. D., Lee, T. H., et al. (2006). Direct electrical detection of DNA synthesis. Proceedings of the National Academy of Sciences of the United States of America, 103, 6466–6470.

    Article  PubMed  CAS  Google Scholar 

  37. Albert, T. J., Molla, M. N., Muzny, D. M., Nazareth, L., Wheeler, D., et al. (2007). Direct selection of human genomic loci by microarray hybridization. Nat Methods, 4, 903–905.

    Article  PubMed  CAS  Google Scholar 

  38. Choi, M., Scholl, U. I., Ji, W., Liu, T., Tikhonova, I. R., et al. (2009). Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proceedings of the National Academy of Sciences of the United States of America, 106, 19096–19101.

    Article  PubMed  CAS  Google Scholar 

  39. Gnirke, A., Melnikov, A., Maguire, J., Rogov, P., LeProust, E. M., et al. (2009). Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nature Biotechnology, 27, 182–189.

    Article  PubMed  CAS  Google Scholar 

  40. Hodges, E., Xuan, Z., Balija, V., Kramer, M., Molla, M. N., et al. (2007). Genome-wide in situ exon capture for selective resequencing. Nature Genetics, 39, 1522–1527.

    Article  PubMed  CAS  Google Scholar 

  41. Porreca, G. J., Zhang, K., Li, J. B., Xie, B., Austin, D., et al. (2007). Multiplex amplification of large sets of human exons. Nat Methods, 4, 931–936.

    Article  PubMed  CAS  Google Scholar 

  42. The Cancer Genome Atlas Research Network (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455, 1061–1068.

    Article  CAS  Google Scholar 

  43. Bardelli, A., Parsons, D. W., Silliman, N., Ptak, J., Szabo, S., et al. (2003). Mutational analysis of the tyrosine kinome in colorectal cancers. Science, 300, 949.

    Article  PubMed  CAS  Google Scholar 

  44. Greenman, C., Stephens, P., Smith, R., Dalgliesh, G. L., Hunter, C., et al. (2007). Patterns of somatic mutation in human cancer genomes. Nature, 446, 153–158.

    Article  PubMed  CAS  Google Scholar 

  45. Jones, S., Zhang, X., Parsons, D. W., Lin, J. C., Leary, R. J., et al. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 321, 1801–1806.

    Article  PubMed  CAS  Google Scholar 

  46. Parsons, D. W., Jones, S., Zhang, X., Lin, J. C., Leary, R. J., et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science, 321, 1807–1812.

    Article  PubMed  CAS  Google Scholar 

  47. Sjoblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., et al. (2006). The consensus coding sequences of human breast and colorectal cancers. Science, 314, 268–274.

    Article  PubMed  Google Scholar 

  48. Wood, L. D., Parsons, D. W., Jones, S., Lin, J., Sjoblom, T., et al. (2007). The genomic landscapes of human breast and colorectal cancers. Science, 318, 1108–1113.

    Article  PubMed  CAS  Google Scholar 

  49. Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., et al. (2009). Recurring mutations found by sequencing an acute myeloid leukemia genome. The New England Journal of Medicine, 361, 1058–1066.

    Article  PubMed  CAS  Google Scholar 

  50. Fredman, D., White, S. J., Potter, S., Eichler, E. E., Den Dunnen, J. T., et al. (2004). Complex SNP-related sequence variation in segmental genome duplications. Nature Genetics, 36, 861–866.

    Article  PubMed  CAS  Google Scholar 

  51. Druker, B. J. (2008). Translation of the Philadelphia chromosome into therapy for CML. Blood, 112, 4808–4817.

    Article  PubMed  CAS  Google Scholar 

  52. Park, J. W., Neve, R. M., Szollosi, J., & Benz, C. C. (2008). Unraveling the biologic and clinical complexities of HER2. Clinical Breast Cancer, 8, 392–401.

    Article  PubMed  CAS  Google Scholar 

  53. Campbell, P. J., Stephens, P. J., Pleasance, E. D., O’Meara, S., Li, H., et al. (2008). Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genetics, 40, 722–729.

    Article  PubMed  CAS  Google Scholar 

  54. Stephens, P. J., McBride, D. J., Lin, M. L., Varela, I., Pleasance, E. D., et al. (2009). Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature, 462, 1005–1010.

    Article  PubMed  CAS  Google Scholar 

  55. Beck, S., & Rakyan, V. K. (2008). The methylome: approaches for global DNA methylation profiling. Trends in Genetics, 24, 231–237.

    Article  PubMed  CAS  Google Scholar 

  56. Feinberg, A. P. (2007). Phenotypic plasticity and the epigenetics of human disease. Nature, 447, 433–440.

    Article  PubMed  CAS  Google Scholar 

  57. Banerjee, H. N., & Verma, M. (2009). Epigenetic mechanisms in cancer. Biomarkers Medicine, 3, 14.

    Google Scholar 

  58. Lister, R., & Ecker, J. R. (2009). Finding the fifth base: genome-wide sequencing of cytosine methylation. Genome Research, 19, 959–966.

    Article  PubMed  CAS  Google Scholar 

  59. Ball, M. P., Li, J. B., Gao, Y., Lee, J. H., LeProust, E. M., et al. (2009). Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nature Biotechnology, 27, 361–368.

    Article  PubMed  CAS  Google Scholar 

  60. Rakyan, V. K., Down, T. A., Thorne, N. P., Flicek, P., Kulesha, E., et al. (2008). An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs). Genome Research, 18, 1518–1529.

    Article  PubMed  CAS  Google Scholar 

  61. Morozova, O., Hirst, M., & Marra, M. A. (2009). Applications of new sequencing technologies for transcriptome analysis. Annual Review of Genomics and Human Genetics, 10, 135–151.

    Article  PubMed  CAS  Google Scholar 

  62. Sultan, M., Schulz, M. H., Richard, H., Magen, A., Klingenhoff, A., et al. (2008). A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome. Science, 321, 956–960.

    Article  PubMed  CAS  Google Scholar 

  63. Friedel, C. C., & Dolken, L. (2009). Metabolic tagging and purification of nascent RNA: implications for transcriptomics. Molecular Biosystems, 5, 1271–1278.

    Article  PubMed  CAS  Google Scholar 

  64. Klein, C. A. (2009). Parallel progression of primary tumours and metastases. Nature Reviews. Cancer, 9, 302–312.

    Article  PubMed  CAS  Google Scholar 

  65. Campbell, P. J., Yachida, S., Mudie, L. J., Stephens, P. J., Pleasance, E. D., et al. (2010). The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature, 467, 1109–1113.

    Article  PubMed  CAS  Google Scholar 

  66. Ding, L., Ellis, M. J., Li, S., Larson, D. E., Chen, K., et al. (2010). Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature, 464, 999–1005.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Michelle Hussong for technical assistance. This work was supported by the Bundesministerium fuer Bildung und Forschung (BMBF)–project Mutanom (01GS08105), Intestinal Modifiers (01GS08111), and Predict (0315428A).

Author information

Authors and Affiliations

  1. Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195, Berlin, Germany

    Michal R. Schweiger, Martin Kerick, Bernd Timmermann & Melanie Isau

  2. Department of Biology, Free University Berlin, Chemistry and Pharmacy, Takustrasse 3, 14195, Berlin, Germany

    Melanie Isau

Authors
  1. Michal R. Schweiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Kerick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bernd Timmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Melanie Isau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michal R. Schweiger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schweiger, M.R., Kerick, M., Timmermann, B. et al. The power of NGS technologies to delineate the genome organization in cancer: from mutations to structural variations and epigenetic alterations. Cancer Metastasis Rev 30, 199–210 (2011). https://doi.org/10.1007/s10555-011-9278-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-011-9278-z

Keywords

Search

Navigation