Identification of a novel retrovirus in prostate tumors of patients homozygous for the R462Q mutation in the HPC1 gene.
ASCO, 2006 Abstract No:304

E. Klein, A. Urisman, R. Molinaro, N. Fischer, S. Plummer, G. Casey, D. Ganem, J. DeRisi, R. Silverman

Introduction: Epidemiologic and genetic evidence suggest the possibility that prostate cancer may be an infectious disease.

HPC1 encodes for RNaseL, a unique antiviral protein activated by viral infection and interferon. Mutations and variants that impair function of RNase L, particularly the SNP R462Q, have been proposed as susceptibility factors for prostate cancer.

Given the role of this gene in viral defense, we explored the possibility that a viral infection might contribute to prostate cancer in men homozygous for R462Q.

Methods: We isolated total and polyA+ mRNA from peripheral zone tumors of 86 radical prostatectomy specimens. Corresponding randomly amplified cDNA was assayed for the presence of viral sequences by hybridization to a DNA microarray composed of oligonucleotides corresponding to more than 5,000 conserved sequences from all known viruses. Tissue localization studies were performed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).

Results: The presence of novel retroviral sequences was revealed in 9 of 20 (45%) men homozygous for R462Q, compared to only 1 (1.5%) of 66 wild type and heterozygous men. Full-length viral genomes were cloned and sequenced from the tumor of 2 R462Q homozygotes. The isolated virus, tentatively named XMRV, is closely related to xenotropic murine leukemia viruses but its sequence is distinct from all known members of this group.

Comparison of gag and pol sequences from different tumor isolates suggested infection with the same virus in all cases, yet sequence variation was consistent with the infections being independently acquired.

FISH and IHC localized the virus to stromal cells adjacent to tumor foci, and in vitro experiments demonstrated a related LnCAP-derived isolate to be replication competent.

Conclusions: These data provide the first demonstration that xenotropic MuLV-related viruses can produce an authentic human infection, and strongly implicate RNase L activity in the prevention or clearance of infection in vivo.

These findings also suggest the possible relationship between exogenous infection and development of prostate cancer in genetically susceptible individuals.