Merkel Cell Polyomavirus: A Causal Factor in Merkel Cell Carcinoma

Abstract

The RNA viruses hepatitis C virus and human T-cell lymphotropic virus type I (or human T-cell leukaemia virus type 1), and the DNA viruses hepatitis B virus, high-risk human papillomaviruses, human herpes virus-8 (Kaposi’s sarcoma-associated herpes virus) and Epstein Barr virus are acknowledged as carcinogenic to humans. Human polyomaviruses have oncogenic potentials in cell cultures and animal models, but their role in human cancer remains controversial. In 2008, a new polyomavirus member discovered in Merkel cell carcinoma tissue was concordantly named Merkel cell polyomavirus (MCPyV). Subsequent epidemiologic studies have shown that viral DNA is present in approximately 80% of Merkel cell carcinomas investigated and MCPyV positive Merkel cell carcinoma have a higher virus load than non-malignant tissues. In addition, the patients have higher viral antibody levels than controls. Moreover, the viral genome seems monoclonally integrated in the primary tumour and in metastatic cells, and expresses a truncated version of the major oncoprotein, large T-antigen. This C-terminal truncated large T-antigen retains its DnaJ and retinoblastoma binding domains, which are necessary for transformation of cells in vitro, but lacks its DNA helicase activity so that it cannot sustain viral DNA replication. These observations suggest that MCPyV can contribute to Merkel cell carcinoma pathogenesis and may therefore add a new virus to the list of human cancer viruses. Here we present information on the biology of polyomaviruses with special focus on MCPyV, review the role of MCPyV in Merkel cell carcinoma, and discuss the molecular mechanisms by which this virus may induce cancer.