Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse

Lara S. Collier, Corey M. Carlson, Shruthi Ravimohan, Adam J. Dupuy, David A. Largaespada

Research output: Contribution to journalArticlepeer-review

331 Scopus citations

Abstract

Retroviruses, acting as somatic cell insertional mutagens, have been widely used to identify cancer genes in the haematopoietic system and mammary gland. An insertional mutagen for use in other mouse somatic cells would facilitate the identification of genes involved in tumour formation in a wider variety of tissues. Here we report the ability of the Sleeping Beauty transposon to act as a somatic insertional mutagen to identify genes involved in solid tumour formation. A Sleeping Beauty transposon, engineered to elicit loss-of-function or gain-of-function mutations, transposed in all somatic tissues tested and accelerated tumour formation in mice predisposed to cancer. Cloning transposon insertion sites from these tumours revealed the presence of common integration sites, at known and candidate cancer genes, similar to those observed in retroviral mutagenesis screens. Sleeping Beauty is a new tool for unbiased, forward genetic screens for cancer genes in vivo.

Original languageEnglish (US)
Pages (from-to)272-276
Number of pages5
JournalNature
Volume436
Issue number7048
DOIs
StatePublished - Jul 14 2005

Bibliographical note

Funding Information:
Acknowledgements We thank M. Roussel for providing Arf2/2 mice; P. Woll, S. Rosenthal, R. Wang, P. Lobitz, J. Zinggeler and M. Davies for technical assistance; P. Hackett, S. McIvor, S. Ekker, P. Marker and members of the Largaespada laboratory for critical reading of the manuscript; N. Kirchhof for performing the pathology; T. L. Bergemann for providing assistance with statistical analysis; and K. Akagi for performing automated sequence analysis and BLAT searches. T2/Onc transgenic mice were generated by the University of Minnesota Mouse Genetics Laboratory. This work was supported by the Arnold and Mabel Beckman Foundation, the National Institute of Drug Abuse and the National Cancer Institute.

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