title: Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis.
abstract: The evolution of colorectal cancer suggests the involvement of many genes. To identify new drivers of intestinal cancer, we performed insertional mutagenesis using the Sleeping Beauty transposon system in mice carrying germline or somatic Apc mutations. By analyzing common insertion sites (CISs) isolated from 446 tumors, we identified many hundreds of candidate cancer drivers. Comparison to human data sets suggested that 234 CIS-targeted genes are also dysregulated in human colorectal cancers. In addition, we found 183 CIS-containing genes that are candidate Wnt targets and showed that 20 CISs-containing genes are newly discovered modifiers of canonical Wnt signaling. We also identified mutations associated with a subset of tumors containing an expanded number of Paneth cells, a hallmark of deregulated Wnt signaling, and genes associated with more severe dysplasia included those encoding members of the FGF signaling cascade. Some 70 genes had co-occurrence of CIS pairs, clustering into 38 sub-networks that may regulate tumor development.
authors: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, UK.
authors: H Nikki
authors: HN
authors: March
authors: Alistair G
authors: AG
authors: Rust
authors: Nicholas A
authors: NA
authors: Wright
authors: Jelle
authors: J
authors: ten Hoeve
authors: Jeroen
authors: J
authors: de Ridder
authors: Matthew
authors: M
authors: Eldridge
authors: Louise
authors: L
authors: van der Weyden
authors: Anton
authors: A
authors: Berns
authors: Jules
authors: J
authors: Gadiot
authors: Anthony
authors: A
authors: Uren
authors: Richard
authors: R
authors: Kemp
authors: Mark J
authors: MJ
authors: Arends
authors: Lodewyk F A
authors: LF
authors: Wessels
authors: Douglas J
authors: DJ
authors: Winton
authors: David J
authors: DJ
authors: Adams
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D052138:Genes, Neoplasm; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009010:Monte Carlo Method; D016254:Mutagenesis, Insertional; D015398:Signal Transduction; D019895:Transposases; D047368:Tumor Burden; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D047908:Intracellular Signaling Peptides and Proteins; D051176:beta Catenin; D019895:Transposases; C494471:sleeping beauty transposase, human