The case for BK polyomavirus as a cause of bladder cancer

Abstract

In 2014, the International Agency for Research on Cancer judged Merkel cell polyomavirus (MCPyV) to be a probable human carcinogen. BK polyomavirus (BKPyV, a distant cousin of MCPyV) was ruled a possible carcinogen. In this review, we argue that it has recently become reasonable to view both of these viruses as known human carcinogens. In particular, several complementary lines of evidence support a causal role for BKPyV in the development of bladder carcinomas affecting organ transplant patients. The expansion of inexpensive deep sequencing has opened new approaches to investigating the important question of whether BKPyV causes urinary tract cancers in the general population.

Figure 1.

Models of polyomavirus (PyV) contribution to carcinogenesis. Persistent direct mechanism: PyV infects an epithelial cell and, through the expression of viral oncogenes and promotion of cellular genome instability, transforms the cell. In the absence of immune-mediated tumor cell death the transformed cell grows into a PyV-positive tumor. Transient direct mechanism (also known as “hit-and-run” or “covert” pathogenesis): virus-mediated cellular genome instability promotes the accumulation of driver mutations (gold stars), eventually enabling a population of tumor cells to lose the expression of viral oncogenes. Cells expressing viral oncogenes are killed through immune surveillance leading to a PyV-negative tumor. Indirect mechanism: PyV infects an endothelial cell adjacent to a pre-malignant epithelial cell. The infected endothelial cell expresses cytokines that recruit tumor-promoting immune cells. The pre-malignant epithelial cell undergoes transformation and grows into a PyV-negative tumor.