Introduction: In the United States, Merkel cell polyomavirus (MCV or MCPyV) infection (as assessed by seroprevalence) ranges from 22% to 88%, with lower rates in children and higher rates in adults. MCV is a stable, nonenveloped DNA virus found in the skin. Transmission of MCV is not fully characterized, but possible transmission through personal contact via saliva or skin has been suggested. MCV establishes a chronic, lifelong, symptomless infection in a large majority of healthy individuals. MCV was discovered in 2008 when nonhuman DNA was detected in human Merkel cell carcinoma cells.
Methods: The National Toxicology Program (NTP) conducted a cancer hazard evaluation of MCV infection for possible listing in the Report on Carcinogens (RoC). The evaluation included the findings from studies reported in the 2008 IARC monograph and from a search for all literature related to MCV. For each cancer site, the evidence from human and mechanistic studies was integrated, considering the following guidelines: Hill’s characteristics of causality, multicausality epidemiology issues, and concepts of direct and indirect carcinogenesis proposed by several virus experts. Finally, the RoC’s listing criteria were applied to the assessment to reach an overall cancer hazard conclusion.
Results and Discussion: Epidemiological, clinical, and molecular studies demonstrated evidence of a causal association between MCV and Merkel cell carcinoma, a rare cancer most commonly observed in the elderly and in immunosuppressed individuals. This association was seen in studies of populations in different geographical areas. Case-control studies and a nested case-control study found consistent evidence of elevated risk estimates among MCV-infected individuals. Risk estimates were highest among those with high levels of anti-MCV antibodies. Clinical studies found significantly higher MCV antibody levels in MCV-positive Merkel cell carcinoma cases, and case series studies found MCV DNA integrated into tumors. Molecular studies in humans found MCV monoclonally integrated into the cellular genome of tumor cells, providing evidence that virus infection precedes cancer.
Mechanistic studies support the epidemiological evidence. Integration of MCV DNA can lead to the expression of two proteins, including a large T (LT) antigen and a small T antigen, which are required for transformation of the host cell into a cancer cell and for proliferation and survival of the cancer cells. The mutated LT antigen prevents viral replication and allows the virus to evade immune detection. Only the mutated, integrated form of MCV is associated with carcinogenicity, which may explain why only a small percentage of infected individuals develop cancer.
NTP Hazard Conclusion and Significance: The conclusion of the cancer hazard evaluation was that MCV should be listed as known to be a human carcinogen in the RoC. The Secretary of Health and Human Services approved the listing of MCV in the 14th RoC. The rationale for the listing was sufficient evidence from studies in humans (human cancer, clinical, and molecular) and supporting mechanistic data. Globally, MCV is estimated to be responsible for approximately 10,000 cancers per year.