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Originally published in Science Express on 26 February 2009
Science 27 March 2009:
Vol. 323. no. 5922, pp. 1747 - 1750
DOI: 10.1126/science.1163040
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Reports

A Transposon-Based Genetic Screen in Mice Identifies Genes Altered in Colorectal Cancer

Timothy K. Starr,1* Raha Allaei,1 Kevin A. T. Silverstein,2 Rodney A. Staggs,2 Aaron L. Sarver,2 Tracy L. Bergemann,3 Mihir Gupta,4 M. Gerard O'Sullivan,5 Ilze Matise,5 Adam J. Dupuy,6 Lara S. Collier,7 Scott Powers,8 Ann L. Oberg,9 Yan W. Asmann,9 Stephen N. Thibodeau,9 Lino Tessarollo,10 Neal G. Copeland,11 Nancy A. Jenkins,11 Robert T. Cormier,12 David A. Largaespada1*

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.

1 Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
2 Department of Biostatistics and Informatics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
3 Department of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
4 Department of Physical and Chemical Biology, Harvard College, Cambridge, MA 02138, USA.
5 College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
6 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
7 School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.
8 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
9 Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
10 Neural Development Group, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI), Frederick, MD 21702, USA.
11 Institute of Molecular and Cell Biology, 138673 Singapore.
12 University of Minnesota Medical School, Duluth, MN 55812, USA.

* To whom correspondence should be addressed. E-mail: star0044{at}umn.edu (T.K.S.); larga002{at}umn.edu (D.A.L.)

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A Modified Sleeping Beauty Transposon System That Can Be Used to Model a Wide Variety of Human Cancers in Mice.
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