Insertional mutagenesis in mice deficient for p15Ink4b, p16Ink4a, p21Cip1, and p27Kip1 reveals cancer gene interactions and correlations with tumor phenotypes.
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.
Kool
Jaap
J
Division of Molecular Genetics, The Centre of Biomedical Genetics, Academic Medical Center and Cancer Genomics Centre, Netherlands Cancer Institute, 1066CX, Amsterdam, the Netherlands.
Uren
Anthony G
AG
Martins
Carla P
CP
Sie
Daoud
D
de Ridder
Jeroen
J
Turner
Geoffrey
G
van Uitert
Miranda
M
Matentzoglu
Konstantin
K
Lagcher
Wendy
W
Krimpenfort
Paul
P
Gadiot
Jules
J
Pritchard
Colin
C
Lenz
Jack
J
Lund
Anders H
AH
Jonkers
Jos
J
Rogers
Jane
J
Adams
David J
DJ
Wessels
Lodewyk
L
Berns
Anton
A
van Lohuizen
Maarten
M
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
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