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Harnessing transposons for cancer gene discovery

Nature Reviews Cancer volume 10, pages 696–706 (2010)Cite this article

Subjects

Key Points

  • Transposon-based insertional mutagenesis (TIM) can be used to model many types of cancer in mice and facilitates the rapid identification of genes that cause cancer.

  • Comparison of the genes mutated by TIM with the genes mutated in human cancer can help to discriminate between those that are driver and those that are passenger mutations in human cancer.

  • TIM can identify new human cancer genes that have so far been missed in human cancer genome sequencing studies, that are difficult to identify because they are epigenetically regulated and that are located in large amplified or deleted regions.

  • TIM induces tumours at all stages of tumour progression, sometimes in a single animal. By identifying the genes mutated by TIM at each stage of progression it might be possible to determine the order in which the mutations were acquired and whether they are involved in tumour initiation, progression and metastasis.

  • Mouse cancer models induced by TIM provide a plethora of new models for studying the biology of cancer and for testing new cancer therapeutics before they go into the clinic.

Abstract

Recently, it has become possible to mobilize the Tc1/mariner transposon, Sleeping Beauty (SB), in mouse somatic cells at frequencies high enough to induce cancer. Tumours result from SB insertional mutagenesis of cancer genes, thus facilitating the identification of the genes and signalling pathways that drive tumour formation. A conditional SB transposition system has also been developed that makes it possible to limit where SB mutagenesis occurs, providing a means to selectively model many types of human cancer. SB mutagenesis has already identified a large collection of known cancer genes in addition to a plethora of new candidate cancer genes and potential drug targets.

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Figure 1: SB structure and mechanism of transposition.
Figure 2: T2/Onc2 can deregulate the expression of oncogenes or inactivate expression of tumour suppressor genes.
Figure 3: High copy T2/Onc2 transgenic lines.
Figure 4: Two Rosa26 SB transposase knock-in alleles.
Figure 5: Barcoded splinkerette PCR amplification and deep sequencing.
Figure 6: Breeding scheme used for mobilizing SB in a sensitized mouse genetic background.

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Acknowledgements

The authors would like to thank S. C. Lee for help with the figures and members of their laboratory for helpful comments on the Review. Support was provided by the Biomedical Research Council (BMRC), Agency for Science and Technology and Research (A*STAR), Singapore.

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  1. Genomics and Genetics Division, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Proteos, 138673, Singapore

    Neal G. Copeland & Nancy A. Jenkins

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Copeland, N., Jenkins, N. Harnessing transposons for cancer gene discovery. Nat Rev Cancer 10, 696–706 (2010). https://doi.org/10.1038/nrc2916

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