• Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Prostate Cancer Institute, Biosciences Research Building, National University of Ireland Galway, Dangan, Corrib Village, Galway, Ireland, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057-1465, USA, Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA, Department of Radiation Oncology, Galway University Hospital, Galway, Ireland and Viral Oncology, Center for Cancer and Metabolism, Stanford Research Institute International, Menlo Park, CA 94025, USA.
• Prostate Cancer Institute, Biosciences Research Building, National University of Ireland Galway, Dangan, Corrib Village, Galway, Ireland.
• Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057-1465, USA.
• Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
• Prostate Cancer Institute, Biosciences Research Building, National University of Ireland Galway, Dangan, Corrib Village, Galway, Ireland, Department of Radiation Oncology, Galway University Hospital, Galway, Ireland and.
• Viral Oncology, Center for Cancer and Metabolism, Stanford Research Institute International, Menlo Park, CA 94025, USA.
• Prostate Cancer Institute, Biosciences Research Building, National University of Ireland Galway, Dangan, Corrib Village, Galway, Ireland, sharon.glynn@nuigalway.ie.

Aberrant expression of subgroup k human endogenous retroviruses (HERV-K) has been observed in prostate cancer. This subgroup is unique because it encodes sequences in the human genome containing open reading frames for near intact retroviruses. We hypothesized that HERV-K reactivation could serve as a non-invasive early disease detection marker for prostate cancer. We evaluated HERV-K gag messenger RNA (mRNA) expression in blood samples of African-American and European-American men using a case-control design via quantitative real-time PCR. Additionally, we examined HERV-K envelope protein expression in prostate tumors by immunohistochemistry. HERV-K envelope protein was commonly upregulated in prostate tumors, but more so in tumors of African-American than European-American patients (61% versus 40%, P < 0.01). Examining HERV-K gag expression in peripheral blood mononuclear cells (PBMC) from 294 cases and 135 healthy men, we found that the abundance of HERV-K gag message was significantly higher in cases than controls and was associated with increased plasma interferon-γ. Men with gag expression in the highest quartile had >12-fold increased odds {odds ratio = 12.87 [95% confidence interval 6.3-26.25]} of being diagnosed with prostate cancer than those in the lowest quartile. Moreover, our results showed that HERV-K expression may perform better as a disease biomarker in older than younger men (whereas the sensitivity of prostate-specific antigen (PSA) testing decreases with age) and in men with a smoking history compared with never smokers. Combining non-invasive HERV-K testing with PSA testing may improve the efficacy of prostate cancer detection specifically among older men and smokers who tend to develop a more aggressive disease.