This schematic depicts the two major causes of MCC, their prevalence, differences in their potential immune targets, and frequencies of response to immune therapy. Top: Differences in MCC prevalence – US/Europe vs. Australia. Left: Virus-induced tumorigenesis – The highly prevalent Merkel cell polyomavirus (MCPyV) is often found on normal skin. Rarely, MCPyV will integrate into the host genome and through a separate rare event, large T will become truncated (tLT; depicted by red X's) prior its C-terminal. Expresssion of the sT and tLT viral oncogenes is tumorigenic through multiple pathways including inhibition of wild-type cellular Rb (see text). Right: UV-induced tumorigenesis – Sun exposure results in the generation of many UV-signature mutations (C->T mutations). The most common of which are in Rb and p53. Rb is frequently found to be inactivated in MCC tumors (67%). Mutation of p53 includes both activating and inactivating mutations. References (16, 18-21, 40-43, 71-75)