A transposon-based genetic screen in mice identifies genes altered in colorectal cancer

Timothy K. Starr, Raha Allaei, Kevin A.T. Silverstein, Rodney A. Staggs, Aaron L. Sarver, Tracy L. Bergemann, Mihir Gupta, M. Gerard O'Sullivan, Ilze Matise, Adam J. Dupuy, Lara S. Collier, Scott Powers, Ann L. Oberg, Yan W. Asmann, Stephen N. Thibodeau, Lino Tessarollo, Neal G. Copeland, Nancy A. Jenkins, Robert T. Cormier, David A. Largaespada

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Abstract

Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.

Original languageEnglish (US)
Pages (from-to)1747-1750
Number of pages4
JournalScience
Volume323
Issue number5922
DOIs
StatePublished - Mar 27 2009

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Starr, T. K., Allaei, R., Silverstein, K. A. T., Staggs, R. A., Sarver, A. L., Bergemann, T. L., Gupta, M., Gerard O'Sullivan, M., Matise, I., Dupuy, A. J., Collier, L. S., Powers, S., Oberg, A. L., Asmann, Y. W., Thibodeau, S. N., Tessarollo, L., Copeland, N. G., Jenkins, N. A., Cormier, R. T., & Largaespada, D. A. (2009). A transposon-based genetic screen in mice identifies genes altered in colorectal cancer. Science, 323(5922), 1747-1750. https://doi.org/10.1126/science.1163040