Journal
CANCER RESEARCH
Volume 70, Issue 2, Pages 520-531Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-2736
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Funding
- Netherlands Organization for Scientific Research (NWO)
- Netherlands Genomics Initiative/NWO
- Netherlands Genomics Initiative BSIK
- Netherlands Genomics Initiative
- Cancer Research UK
- Wellcome Trust
- Medical Research Council [MC_UP_A652_1001] Funding Source: researchfish
- MRC [MC_UP_A652_1001] Funding Source: UKRI
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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.
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