title: Insertional mutagenesis in mice deficient for p15Ink4b, p16Ink4a, p21Cip1, and p27Kip1 reveals cancer gene interactions and correlations with tumor phenotypes.
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, 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.
authors.affiliation: Division of Molecular Genetics, The Centre of Biomedical Genetics, Academic Medical Center and Cancer Genomics Centre, Netherlands Cancer Institute, 1066CX, Amsterdam, the Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Kool
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Uren
authors.forename: Carla P
authors.initials: CP
authors.lastname: Martins
authors.forename: Daoud
authors.initials: D
authors.lastname: Sie
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Ridder
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Turner
authors.forename: Miranda
authors.initials: M
authors.lastname: van Uitert
authors.forename: Konstantin
authors.initials: K
authors.lastname: Matentzoglu
authors.forename: Wendy
authors.initials: W
authors.lastname: Lagcher
authors.forename: Paul
authors.initials: P
authors.lastname: Krimpenfort
authors.forename: Jules
authors.initials: J
authors.lastname: Gadiot
authors.forename: Colin
authors.initials: C
authors.lastname: Pritchard
authors.forename: Jack
authors.initials: J
authors.lastname: Lenz
authors.forename: Anders H
authors.initials: AH
authors.lastname: Lund
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Jane
authors.initials: J
authors.lastname: Rogers
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
mesh_terms: D000818:Animals; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000172:deficiency / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000172:deficiency / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics; D005260:Female; D009052:Leukemia Virus, Murine / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics; D008223:Lymphoma / Q000235:genetics; D008297:Male; D051379:Mice; D016254:Mutagenesis, Insertional / Q000235:genetics*; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; C417743:Cdkn2a protein, mouse; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27