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

• Published in: Science (American Association for the Advancement of Science) Vol. 323; no. 5922; pp. 1747 - 1750
• Main Authors: Starr, Timothy K, Allaei, Raha, Silverstein, Kevin A.T, Staggs, Rodney A, Sarver, Aaron L, Bergemann, Tracy L, Gupta, Mihir, O'Sullivan, M. Gerard, Matise, Ilze, Dupuy, Adam J, Collier, Lara S, Powers, Scott, Oberg, Ann L, Asmann, Yan W, Thibodeau, Stephen N, Tessarollo, Lino, Copeland, Neal G, Jenkins, Nancy A, Cormier, Robert T, Largaespada, David A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 27.03.2009; The American Association for the Advancement of Science
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenoma - genetics; Adenoma - pathology; Animals; Biological and medical sciences; Carcinoma in Situ - genetics; Carcinoma in Situ - pathology; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Crosses, Genetic; DNA; DNA Transposable Elements; Gastroenterology. Liver. Pancreas. Abdomen; Gene Amplification; Gene Deletion; Gene expression; Gene Expression Regulation, Neoplastic; Genes, APC; Genes, Neoplasm; Genetic mutation; Genetic screening; Genetic Testing; Genetic transposition; Genetics; Human genetics; Humans; Medical sciences; Mice; Mice, Transgenic; Monte Carlo Method; Mutation; Oligonucleotide Array Sequence Analysis; PTEN Phosphohydrolase - genetics; Rodents; Smad4 Protein - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transgenic animals; Transposons; Tumors; Rectal disease; Transposon; Rodentia; Colorectal cancer; Malignant tumor; Colonic disease; Vertebrata; Mammalia; Mouse; Animal; Digestive diseases; Intestinal disease; Cancer
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1163040

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.