Distinct Gene Expression Profiles of Viral- and Nonviral-Associated Merkel Cell Carcinoma Revealed by Transcriptome Analysis

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCCs, may drive tumorigenesis via viral T antigens. However, the mechanisms underlying pathogenesis in MCPyV-negative MCCs remain poorly understood. To nominate genes contributing to the pathogenesis of MCPyV-negative MCCs, we performed DNA microarray analysis on 30 MCCs. The MCPyV status of MCCs was determined by PCR for viral DNA and RNA. A total of 1,593 probe sets were differentially expressed between MCPyV-negative and MCPyV-positive MCCs, with significant differential expression defined as at least a 2-fold change in either direction and a P-value p0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8 þ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may have an important role in the tumorigenesis of MCPyV-negative MCCs. Functional and clinical validation studies are needed to determine whether this tumorsuppressor pathway represents an avenue for targeted therapy.