Molecular characterization of virus-positive and virusnegativein Merkel cell carcinoma

Background and Aim : Merkel cell carcinoma (MCC) is a highly invasive neuroendocrinecarcinoma of the skin. Risk factors for developing MCC contain advanced age, light skinassociated with over exposure to sunlight, and a variety of immunodeficiency conditions. In ۲۰۰۸,Merkel cell polyomavirus (MCPyV) was first identified by Southern blot in some but not all MCCtumors with integration of viral DNA that occurs at several different chromosomal sites.Methods : Importantly, a pattern of identical clonal integration was identified in one primarytumor and corresponding metastatic lymph node. This important insight suggested that integrationof the viral DNA was an early event in virus-positive MCC oncogenesis. MCPyV usually infectsmost people at young age and leads to asymptomatic and lifelong infection, which is manifestedby the persistent presence of antibodies to the VP۱ viral envelope protein. MCPyV DNA is easilydetected in the skin, but the cell type in which the virus replicates in vivo has not been identified.Since the initial discovery of MCPyV, it has become increasingly clear that virus-positive MCChas a different cause than virus-positive, UV-associated, MCC.Results : Virus-positive MCC expresses the viral oncogenes large T antigen (LT) and small Tantigen (ST) and the tumor genome usually includes very few mutations in cellular oncogenes andtumor suppressor genes. In contrast, studies using whole exome or targeted hybrid capturesequencing have showed that virus-negative MCC has an exceptionally high somatic mutationload predominated by UV-mediated mutations with frequent mutations in RB۱, TP۵۳, NOTCH۱,and FAT۱.Conclusion : Whole genome sequencing (WGS) of MCC confirmed virus-positive MCC shows aglobally lower, non-UV-mediated, mutation burden as well as few somatic copy numberamplifications, deletions, and rearrangements compared to virus-negative MCC, while offeringnew insights into virus integration structure and mechanism.