Insertional Mutagenesis in Mice Deficient for p15(Ink4b), p16(Ink4a), p21(Cip1), and p27(Kip1) Reveals Cancer Gene Interactions and Correlations with Tumor Phenotypes

Jaap Kool, Anthony G. Uren, Carla P. Martins, Daoud Sie, Jeroen de Ridder, Geoffrey Turner, Miranda van Uitert, Konstantin Matentzoglu, Wendy Lagcher, Paul Krimpenfort, Jules Gadiot, Colin Pritchard, Jack Lenz, Anders H. Lund, Jos Jonkers, Jane Rogers, David J. Adams, Lodewyk Wessels, Anton Berns, Maarten van Lohuizen

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    29 Citations (Scopus)


    The cyclin dependent kinase (CDK) inhibitors p15, p16, p21, and p27 are frequently deleted, silenced, or downregulated in many malignancies. Inactivation of CDK inhibitors predisposes mice to tumor development, showing that these genes function as tumor suppressors. Here, we describe high-throughput murine leukemia virus insertional mutagenesis screens in mice that are deficient for one or two CDK inhibitors. We retrieved 9,117 retroviral insertions from 476 lymphomas to define hundreds of loci that are mutated more frequently than expected by chance. Many of these loci are skewed toward a specific genetic context of predisposing germline and somatic mutations. We also found associations between these loci with gender, age of tumor onset, and lymphocyte lineage (B or T cell). Comparison of retroviral insertion sites with single nucleotide polymorphisms associated with chronic lymphocytic leukemia revealed a significant overlap between the datasets. Together, our findings highlight the importance of genetic context within large-scale mutation detection studies, and they show a novel use for insertional mutagenesis data in prioritizing disease-associated genes that emerge from genome-wide association studies. Cancer Res; 70(2); 520-31. (C)2010 AACR
    Original languageEnglish
    Pages (from-to)520-531
    Number of pages12
    JournalCancer research
    Issue number2
    Publication statusPublished - 15 Jan 2010


    • Animals
    • Cyclin-Dependent Kinase Inhibitor Proteins/deficiency
    • Cyclin-Dependent Kinase Inhibitor p15/deficiency
    • Cyclin-Dependent Kinase Inhibitor p16/deficiency
    • Cyclin-Dependent Kinase Inhibitor p21/deficiency
    • Cyclin-Dependent Kinase Inhibitor p27/deficiency
    • Female
    • Leukemia Virus, Murine/genetics
    • Leukemia, Lymphocytic, Chronic, B-Cell/genetics
    • Lymphoma/genetics
    • Male
    • Mice
    • Mutagenesis, Insertional/genetics
    • NIH 3T3 Cells
    • Neoplasms, Experimental/genetics
    • Polymorphism, Single Nucleotide

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