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

TY - JOUR

T1 - Insertional mutagenesis in mice deficient for p15Ink4b, p16Ink4a, p21Cip1, and p27Kip1 reveals cancer gene interactions and correlations with tumor phenotypes

AU - Kool, Jaap

AU - Uren, Anthony G

AU - Martins, Carla P

AU - Sie, Daoud

AU - de Ridder, Jeroen

AU - Turner, Geoffrey

AU - van Uitert, Miranda

AU - Matentzoglu, Konstantin

AU - Lagcher, Wendy

AU - Krimpenfort, Paul

AU - Gadiot, Jules

AU - Pritchard, Colin

AU - Lenz, Jack

AU - Lund, Anders H

AU - Jonkers, Jos

AU - Rogers, Jane

AU - Adams, David J

AU - Wessels, Lodewyk

AU - Berns, Anton

AU - van Lohuizen, Maarten

PY - 2010/1/15

Y1 - 2010/1/15

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-09-2736

DO - 10.1158/0008-5472.CAN-09-2736

M3 - Journal article

C2 - 20068150

SN - 0008-5472

VL - 70

SP - 520

EP - 531

JO - Cancer Research

JF - Cancer Research

IS - 2

ER -