Large-scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks

Anthony G. Uren, Jaap Kool, Konstantin Matentzoglu, Jeroen de Ridder, Jenny Mattison, Miranda van Uitert, Wendy Lagcher, Daoud Sie, Ellen Tanger, Tony Cox, Marcel Reinders, Tim J. Hubbard, Jane Rogers, Jos Jonkers, Lodewyk Wessels, David J. Adams, Maarten van Lohuizen, Anton Berns

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155 Citations (Scopus)


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
Original languageEnglish
Pages (from-to)727-741
Number of pages15
Issue number4
Publication statusPublished - 16 May 2008


  • Animals
  • Cell Line, Tumor
  • Cloning, Molecular
  • Cyclin-Dependent Kinase Inhibitor p16/genetics
  • Gene Regulatory Networks
  • Genes, Tumor Suppressor
  • Genes, p53
  • Genomics/methods
  • Humans
  • Mice
  • Mice, Knockout
  • Mutagenesis, Insertional
  • Neoplasms/genetics
  • Sequence Analysis, DNA
  • Tumor Suppressor Protein p53/metabolism

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