Insertional Mutagenesis in Mice Deficient for p15Ink4b, p16Ink4a, p21Cip1, and p27Kip1 Reveals Cancer Gene Interactions and Correlations with Tumor Phenotypes

被引:23
作者
Kool, Jaap [3 ,4 ]
Uren, Anthony G. [3 ,4 ]
Martins, Carla P. [3 ,4 ]
Sie, Daoud [2 ]
de Ridder, Jeroen [1 ,5 ]
Turner, Geoffrey [6 ]
van Uitert, Miranda [1 ]
Matentzoglu, Konstantin [3 ,4 ]
Lagcher, Wendy [3 ,4 ]
Krimpenfort, Paul [3 ,4 ]
Gadiot, Jules [3 ,4 ]
Pritchard, Colin [3 ,4 ]
Lenz, Jack [6 ]
Lund, Anders H. [3 ,4 ]
Jonkers, Jos [1 ]
Rogers, Jane [7 ]
Adams, David J. [7 ]
Wessels, Lodewyk [1 ,5 ]
Berns, Anton [1 ,3 ,4 ]
van Lohuizen, Maarten [3 ,4 ]
机构
[1] Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands
[2] Netherlands Canc Inst, Cent Microarray Facil, NL-1066 CX Amsterdam, Netherlands
[3] Netherlands Canc Inst, Canc Genom Ctr, NL-1066 CX Amsterdam, Netherlands
[4] Univ Amsterdam, Acad Med Ctr, Ctr Biomed Genet, Div Mol Genet, NL-1105 AZ Amsterdam, Netherlands
[5] Delft Univ Technol, Fac Elect Engn Math & Comp Sci, Delft, Netherlands
[6] Albert Einstein Coll Med, Bronx, NY 10467 USA
[7] Wellcome Trust Sanger Inst, Hinxton, England
基金
英国惠康基金;
关键词
CONFERS SUSCEPTIBILITY; SUPPRESSOR GENE; N-MYC; PROTEIN; IDENTIFICATION; BREAST; CYCLE; KINASE; INHIBITORS; LEUKEMIA;
D O I
10.1158/0008-5472.CAN-09-2736
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:520 / 531
页数:12
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