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Cancer Res. 2010 Jan 15;70(2):520-31. doi: 10.1158/0008-5472.CAN-09-2736. Epub 2010 Jan 12.

Insertional mutagenesis in mice deficient for p15Ink4b, p16Ink4a, p21Cip1, and p27Kip1 reveals cancer gene interactions and correlations with tumor phenotypes.

Author information

1
Division of Molecular Genetics, The Centre of Biomedical Genetics, Academic Medical Center and Cancer Genomics Centre, Netherlands Cancer Institute, 1066CX, Amsterdam, the Netherlands.

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.

PMID:
20068150
PMCID:
PMC2875110
DOI:
10.1158/0008-5472.CAN-09-2736
[Indexed for MEDLINE]
Free PMC Article

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