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In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer.

ABSTRACT: XMRV, or xenotropic murine leukemia virus (MLV)-related virus, is a novel gammaretrovirus originally identified in studies that analyzed tissue from prostate cancer patients in 2006 and blood from patients with chronic fatigue syndrome (CFS) in 2009. However, a large number of subsequent studies failed to confirm a link between XMRV infection and CFS or prostate cancer. On the contrary, recent evidence indicates that XMRV is a contaminant originating from the recombination of two mouse endogenous retroviruses during passaging of a prostate tumor xenograft (CWR22) in mice, generating laboratory-derived cell lines that are XMRV-infected. To confirm or refute an association between XMRV and prostate cancer, we analyzed prostate cancer tissues and plasma from a prospectively collected cohort of 39 patients as well as archival RNA and prostate tissue from the original 2006 study. Despite comprehensive microarray, PCR, FISH, and serological testing, XMRV was not detected in any of the newly collected samples or in archival tissue, although archival RNA remained XMRV-positive. Notably, archival VP62 prostate tissue, from which the prototype XMRV strain was derived, tested negative for XMRV on re-analysis. Analysis of viral genomic and human mitochondrial sequences revealed that all previously characterized XMRV strains are identical and that the archival RNA had been contaminated by an XMRV-infected laboratory cell line. These findings reveal no association between XMRV and prostate cancer, and underscore the conclusion that XMRV is not a naturally acquired human infection.

SUBMITTER: Lee D

PROVIDER: S-EPMC3445615 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer.

Lee Deanna D Das Gupta Jaydip J Gaughan Christina C Steffen Imke I Tang Ning N Luk Ka-Cheung KC Qiu Xiaoxing X Urisman Anatoly A Fischer Nicole N Molinaro Ross R Broz Miranda M Schochetman Gerald G Klein Eric A EA Ganem Don D Derisi Joseph L JL Simmons Graham G Hackett John J Silverman Robert H RH Chiu Charles Y CY

PloS one 20120918 9

XMRV, or xenotropic murine leukemia virus (MLV)-related virus, is a novel gammaretrovirus originally identified in studies that analyzed tissue from prostate cancer patients in 2006 and blood from patients with chronic fatigue syndrome (CFS) in 2009. However, a large number of subsequent studies failed to confirm a link between XMRV infection and CFS or prostate cancer. On the contrary, recent evidence indicates that XMRV is a contaminant originating from the recombination of two mouse endogenou ...[more]

PMID: 23028701

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Project description:XMRV, or xenotropic murine leukemia virus (MLV)-related virus, is a novel gammaretrovirus originally identified in studies that analyzed tissue from prostate cancer patients in 2006 and blood from patients with chronic fatigue syndrome (CFS) in 2009. However, a large number of subsequent studies failed to confirm a link between XMRV infection and CFS or prostate cancer. On the contrary, recent evidence indicates that XMRV is a contaminant originating from the recombination of two mouse endogenous retroviruses during passaging of a prostate tumor xenograft (CWR22) in mice, generating laboratory-derived cell lines that are XMRV-infected. To confirm or refute an association between XMRV and prostate cancer, we analyzed prostate cancer tissues and plasma from a prospectively collected cohort of 39 patients as well as archival RNA and prostate tissue from the original 2006 study. Despite comprehensive microarray, PCR, FISH, and serological testing, XMRV was not detected in any of the newly collected samples or in archival tissue, although archival RNA remained XMRV-positive. Notably, archival VP62 prostate tissue, from which the prototype XMRV strain is derived, tested negative for XMRV on re-analysis. Analysis of viral genomic and human mitochondrial sequences revealed that all previously characterized XMRV strains are identical and that the archival RNA had been contaminated by an XMRV-infected laboratory cell line. These findings reveal no association between XMRV and prostate cancer, and underscore the conclusion that XMRV is not a naturally acquired human infection. The Virochip microarray (version 5.0, Viro5AGL-60K platform) was used to screen RNA extracts from prostate tissue for XMRV to determine whether there is an association between the virus and prostate cancer. We used the ViroChip microarray to screen 22 archived prostate biopsies extracted in 2006 and 39 prospectively collected prostate biopsies for the virus, Xenotropic Murine Leukemia Virus-Related Virus (XMRV). We used custom-commercial microarrays from Agilent Technologies. The microarray platform GPL11662 consists of 62,976 probes [PMID 21779173], including all of the viral probes from the previous v2.0 (MV), v3.0 (V3) and v4.0 (V4) designs [PMIDs 18768820, 16983602, 16609730, 12429852, 9843981]. For this study, 61 experimental ViroChip microarrays derived from prospectively collected RNA extracted prostate tissue and frozen RNA from archived prostate from a 2006 study were analyzed. Additionally, two XMRV-positive control microarrays from the cell line, 22Rv1, were hybridized, for a total of 63 ViroChip microarrays. Some RNA extracts were enriched for polyadenylated (polyA) transcripts prior to hybridization.

Project description:BackgroundXenotropic murine leukemia virus (MLV)-related virus (XMRV) was initially identified in prostate cancer (PCa) tissue, particularly in the prostatic stromal fibroblasts, of patients homozygous for the RNASEL R462Q mutation. A subsequent study reported XMRV antigens in malignant prostatic epithelium and association of XMRV infection with PCa, especially higher-grade tumors, independently of the RNASEL polymorphism. Further studies showed high prevalence of XMRV or related MLV sequences in chronic fatigue syndrome patients (CFS), while others found no, or low, prevalence of XMRV in a variety of diseases including PCa or CFS. Thus, the etiological link between XMRV and human disease remains elusive. To address the association between XMRV infection and PCa, we have tested prostate tissues and human sera for the presence of viral DNA, viral antigens and anti-XMRV antibodies.ResultsReal-time PCR analysis of 110 PCa (Gleason scores >4) and 40 benign and normal prostate tissues identified six positive samples (5 PCa and 1 non-PCa). No statistical link was observed between the presence of proviral DNA and PCa, PCa grades, and the RNASEL R462Q mutation. The amplified viral sequences were distantly related to XMRV, but nearly identical to endogenous MLV sequences in mice. The PCR positive samples were also positive for mouse mitochondrial DNA by nested PCR, suggesting contamination of the samples with mouse DNA. Immuno-histochemistry (IHC) with an anti-XMRV antibody, but not an anti-MLV antibody that recognizes XMRV, sporadically identified antigen-positive cells in prostatic epithelium, irrespectively of the status of viral DNA detection. No serum (159 PCa and 201 age-matched controls) showed strong neutralization of XMRV infection at 1:10 dilution.ConclusionThe lack of XMRV sequences or strong anti-XMRV neutralizing antibodies indicates no or very low prevalence of XMRV in our cohorts. We conclude that real-time PCR- and IHC-positive samples were due to laboratory contamination and non-specific immune reactions, respectively.

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In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer.

Publications

In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer.

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