None of the four human polymaviruses that were known in early 2008 – JC, BK, KI and WU – had been shown to cause cancer. The subsequent identification of a new polyomavirus associated with Merkel cell carcinoma demonstrates the type of evidence that is required to prove that a virus is oncogenic in humans.
Merkel cell carcinoma (MCC) is a relatively rare human skin cancer, although its incidence has increased in the past twenty years from 500 to 1500 cases per year. This cancer occurs more frequently than expected in individuals who are immunosuppressed, such as those who have received organ transplants or who have AIDS. A similar pattern of susceptibility is also observed for Kaposi’s sarcoma, a tumor that is caused by the herpesvirus HHV-8. Therefore it was suggested that MCC might also be caused by an infectious agent.
To identify the etiologic agent of MCC, the nucleotide sequence of total mRNA from several MCC tumors was determined and compared with the sequence of mRNA from a normal human cell. This analysis revealed that the MCC tumors contained a previously unknown polyomavirus which the authors named Merkel cell polyomavirus (MCV or MCPyV). The viral genome was found to be integrated at different sites in human chromosomal DNA from MCC tumors.
If MCV infection causes MCC, then the viral genome should be present in tumors but not in normal tissues. MCC DNA was found in eight of ten MCC tumors, each obtained from a different patient. The viral genome was not detected in various tissues samples from 59 patients without MCC. Furthermore, the viral genome had integrated into one site in the chromosome of one tumor and a metastasis dervied from it. This observation indicates that integration of the viral genome occurs first, before division of the tumor cells.
In subsequent studies MCV DNA has been detected in 40-85% of the MCC tumors examined. The viral DNA is not found in small cell lung carcinoma, which, like MCC, is also a neuroendocrine carcinoma. MCV particles have also been detected by electron microscopy in the cytoplasm and nucleus of tumor cells from one patient, suggesting ongoing viral replication.
How might MCV cause Merkel cell carcinoma? Expression of the viral protein known as T antigen might be sufficient to transform cells. Alternatively, integration of the viral DNA into human DNA could lead to unregulated synthesis of a protein that transforms cells. To prove that MCV causes Merkel cell carcinoma, it will be necessary to demonstrate that infection with the virus, or transfection with viral DNA, transforms and immortalizes cells in culture.
Feng, H., Shuda, M., Chang, Y., & Moore, P. (2008). Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma Science, 319 (5866), 1096-1100 DOI: 10.1126/science.1152586
Wetzels, C., Hoefnagel, J., Bakkers, J., Dijkman, H., Blokx, W., & Melchers, W. (2009). Ultrastructural Proof of Polyomavirus in Merkel Cell Carcinoma Tumour Cells and Its Absence in Small Cell Carcinoma of the Lung PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0004958