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Journal of Virology, October 2008, p. 9964-9977, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01299-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Integration Site Preference of Xenotropic Murine Leukemia Virus-Related Virus, a New Human Retrovirus Associated with Prostate Cancer

Sanggu Kim,¹ Namshin Kim,^3, Beihua Dong,⁵ David Boren,² Serena A. Lee,² Jaydip Das Gupta,⁵ Christina Gaughan,⁵ Eric A. Klein,⁶ Christopher Lee,³ Robert H. Silverman,⁵ and Samson A. Chow^1,2,3,4*

Biomedical Engineering Interdepartmental Program,¹ Department of Molecular and Medical Pharmacology,² Molecular Biology Institute,³ UCLA AIDS Institute, UCLA School of Medicine, Los Angeles, California 90095,⁴ Department of Cancer Biology, Lerner Research Institute,⁵ Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195⁶

Received 22 June 2008/ Accepted 3 August 2008

Xenotropic murine leukemia virus-related virus (XMRV) is a new human gammaretrovirus identified in prostate cancer tissue from patients homozygous for a reduced-activity variant of the antiviral enzyme RNase L. Neither a casual relationship between XMRV infection and prostate cancer nor a mechanism of tumorigenesis has been established. To determine the integration site preferences of XMRV and the potential risk of proviral insertional mutagenesis, we carried out a genome-wide analysis of viral integration sites in the prostate cell line DU145 after an acute XMRV infection and compared the integration site pattern of XMRV with those found for murine leukemia virus and two human retroviruses, human immunodeficiency virus type 1 and human T-cell leukemia virus type 1. Among all retroviruses analyzed, XMRV has the strongest preference for transcription start sites, CpG islands, DNase-hypersensitive sites, and gene-dense regions; all are features frequently associated with structurally open transcription regulatory regions of a chromosome. Analyses of XMRV integration sites in tissues from prostate cancer patients found a similar preference for the aforementioned chromosomal features. Additionally, XMRV integration sites in cancer tissues were associated with cancer breakpoints, common fragile sites, microRNA, and cancer-related genes, suggesting a selection process that favors certain chromosomal integration sites. In both acutely infected cells and cancer tissues, no common integration site was detected within or near proto-oncogenes or tumor suppressor genes. These results are consistent with a model in which XMRV may contribute to tumorigenicity via a paracrine mechanism.

Published ahead of print on 6 August 2008.

Present address: Korean Bioinformation Center, Korean Research Institute of Bioscience and Technology, Daejeon 305-806, South Korea.