Insertional Mutagenesis in Mice Deficient for P15ink4b, P16ink4a, P21cip1, P27kip1 Reveals Cancer Gene Interactions and Correlations with Tumor Phenotypes
Published in final edited form as: Cancer Res. 2010 January 15; 70(2): 520–531. doi:10.1158/0008-5472.CAN-09-2736. Insertional mutagenesis in mice deficient for p15Ink4b, p16Ink4a, p21Cip1, p27Kip1 reveals cancer gene interactions and correlations with tumor phenotypes Jaap Kool1, Anthony G. Uren1, Carla P. Martins1,7, Daoud Sie2, Jeroen de Ridder3,4, Geoffrey Turner5,8, Miranda van Uitert3, Konstantin Matentzoglu1,9, Wendy Lagcher1, Paul Krimpenfort1, Jules Gadiot1, Colin Pritchard1, Jack Lenz5, Anders H. Lund1,10, Jos Jonkers3, Jane Rogers6,11, David J. Adams6, Lodewyk Wessels3,4, Anton Berns1, and Maarten van Lohuizen1 1Division of Molecular Genetics, The Centre of Biomedical Genetics, Academic Medical Center and Cancer Genomics Centre, Netherlands Cancer Institute, Amsterdam, The Netherlands 2Central Microarray Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands 3Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands 4Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, The Netherlands 5Albert Einstein College of Medicine, Bronx, NY, U.S.A. 6Wellcome Trust Sanger Institute, Hinxton, UK Abstract 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 demonstrating that these genes can act as tumor suppressors. Here we describe high-throughput murine leukemia virus (MuLV) insertional mutagenesis screens in mice deficient for one or a combination of two CDK inhibitors. We retrieved 9117 retroviral insertions from 476 lymphomas and find hundreds of loci that are mutated significantly more frequently than expected by chance. Many of these are skewed toward a specific genetic context of predisposing germline and somatic mutations.
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