title: Large-scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks.
abstract: p53 and p19(ARF) are tumor suppressors frequently mutated in human tumors. In a high-throughput screen in mice for mutations collaborating with either p53 or p19(ARF) deficiency, we identified 10,806 retroviral insertion sites, implicating over 300 loci in tumorigenesis. This dataset reveals 20 genes that are specifically mutated in either p19(ARF)-deficient, p53-deficient or wild-type mice (including Flt3, mmu-mir-106a-363, Smg6, and Ccnd3), as well as networks of significant collaborative and mutually exclusive interactions between cancer genes. Furthermore, we found candidate tumor suppressor genes, as well as distinct clusters of insertions within genes like Flt3 and Notch1 that induce mutants with different spectra of genetic interactions. Cross species comparative analysis with aCGH data of human cancer cell lines revealed known and candidate oncogenes (Mmp13, Slamf6, and Rreb1) and tumor suppressors (Wwox and Arfrp2). This dataset should prove to be a rich resource for the study of genetic interactions that underlie tumorigenesis.
authors.affiliation: Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Uren
authors.forename: Jaap
authors.initials: J
authors.lastname: Kool
authors.forename: Konstantin
authors.initials: K
authors.lastname: Matentzoglu
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Ridder
authors.forename: Jenny
authors.initials: J
authors.lastname: Mattison
authors.forename: Miranda
authors.initials: M
authors.lastname: van Uitert
authors.forename: Wendy
authors.initials: W
authors.lastname: Lagcher
authors.forename: Daoud
authors.initials: D
authors.lastname: Sie
authors.forename: Ellen
authors.initials: E
authors.lastname: Tanger
authors.forename: Tony
authors.initials: T
authors.lastname: Cox
authors.forename: Marcel
authors.initials: M
authors.lastname: Reinders
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Hubbard
authors.forename: Jane
authors.initials: J
authors.lastname: Rogers
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D023281:Genomics / Q000379:methods; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53