The Final Chapter on XMRV and Prostate Cancer
Discovering whether viruses cause cancer is important for public health, since prevention or treatment of these viral infections can avoid a potentially fatal disease. This is underscored by the recent introduction of the Gardasil vaccine to prevent infection by strains of human papillomavirus that can cause cervical cancer in women.
In men, prostate cancer is one of the leading causes of death; risk factors are known, but the exact cause remains elusive. One of the risk factors is a genetic mutation that decreases the activity of a viral defense gene, RNase L, reported to be associated with 13% of prostate cancer cases. This suggests a viral cause for some cases of prostate cancer. This observation formed the basis of a project to hunt for viruses in prostate cancer tissue, leading to the first report of the presence of a gammaretrovirus called xenotropic murine leukemia virus-related virus (XMRV) in prostate cancer, which was predominately found in individuals who had both copies of the lower-activity RNase L gene. This finding was published in 2006 by Urisman and colleagues in PLOS Pathogens. The presence of XMRV was remarkable, since it was the first time that a gammaretrovirus normally found in the mouse was detected in humans. Not surprisingly, this publication attracted considerable attention from the scientific community with an explosion of reports attempting to confirm the association of XMRV with prostate cancer, to understand the biology of XMRV, to determine how XMRV causes prostate cancer, and to develop assays for detection of XMRV exposure to safeguard the blood supply. In 2009, XMRV was also reported in patients diagnosed with chronic fatigue syndrome (CFS), although this finding was not reproduced by subsequent studies. In 2011, concerns about the validity of this 2009 study resulted in a full retraction by the editors of Science (Alberts, 2011).
Despite the controversies in the CFS field, at that time the XMRV prostate cancer story remained an open question. Fast forward to early 2012 – and over a 100 publications later – XMRV was accepted by the majority of the scientific community to be a contaminant with no role in causing prostate cancer. This was due to several studies published in late 2010 and early 2011 demonstrating that XMRV was a laboratory-generated virus (Paprotka et al 2011) and that highly sensitive nucleic acid detection assays were not detecting a bone fide infection of XMRV or related viruses in humans, but instead contamination from a variety of sources including mouse DNA, XMRV plasmid DNA, and XMRV from infected cell lines (see reviews by Sfanos et al 2012 and Groom and Bishop 2012). In the context of these findings, this study in PLOS ONE by Lee and colleagues is significant because it has allowed Charles Chiu from the University of San Francisco along with his collaborators including authors who originally reported the association of XMRV with prostate cancer to set the record straight. Using careful molecular detective work, they found that the original archived prostate cancer tissue was negative for XMRV although the archival extracted RNA from the original study was positive for XMRV. They also failed to demonstrate the presence of XMRV in new prostate cancer samples. In addition, they discovered that the source of XMRV contamination in the archival extracted RNA was from an XMRV-infected cell line used in the laboratory. The inability to confirm their original findings published in PLOS Pathogens represents the final chapter that closes the book on XMRV and its role as a naturally acquired human infection associated with prostate cancer. The PLOS Pathogens paper is retracted today.
The whole saga provides an invaluable lesson to researchers attempting to find associations between viral infections and human diseases such as cancer (see Weiss 2010). It also provides an excellent example of the self-correcting nature and rigour of the scientific process.
REFERENCES
Urisman A, Molinaro RJ, Fisher N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, De Risi JL. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathogens 2006, 2:e25.
Lombardi VC, Ruscetti FW, Das Gupta MA, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009, 326: 585 – 589.
Alberts B. Retraction of Lombardi et al Science 326: 585 – 589. Science 2011, 334: 1636.
Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung HJ, Tepper CG, Hu WS, Fivash MJ, Coffin JM, Pathak VK. Recombinant origin of the retrovirus XMRV. Science 2011, 333: 97 – 101.
Sfanos KS, Aloia AL, De Marzo AM, Rein A. XMRV and prostate cancer – a “final” perspective. Nature Reviews Urology 2012, 9: 111-118
Groom HCT and Bishop KN. The tale of xenotropic murine leukemia virus-related virus. Journal of General Virology. 2012, 93: 915 – 924.
Lee D, Das Gupta J, Gaughan C, Steffan I, Tang N, Luk K-G, Qiu X, Urisman A, Fischer N, Molinaro R, Broz M, Schochetman G, Klein E, Ganem D, DeRisi JL, Simmons G, Hacket J, Silverman R, Chiu CY. In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer. PLoS ONE doi:10.1371/journal.pone.0044954
Weiss RA. A cautionary tale of virus and disease. BMC Biology. 2010, 8: 124
About the Author: Associate Professor Gilda Tachedjian is a virologist and Head of the Retroviral Biology and Antivirals Laboratory at the Centre for Virology, Burnet Institute in Melbourne Australia and a National Health and Medical Research Council (NHMRC) Senior Research Fellow. She is also an academic editor at PLOS ONE and she handled the manuscript described in this post.
Conflicts of Interest:
Gilda Tachedjian is the recipient of grant funding from the Prostate Cancer Foundation of Australia (CG 0710 XMRV in Australian Prostate Cancer)