Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates.,Merkel cell polyomavirus (MCPyV), identified in the majority of MCC, may drive tumorigenesis via viral T antigens.,However, mechanisms underlying pathogenesis in MCPyV-negative MCC remain poorly understood.,To nominate genes contributing to pathogenesis of MCPyV-negative MCC, we performed DNA microarray analysis on 30 MCCs.,MCPyV status of MCCs was determined by PCR for viral DNA and RNA. 1593 probe-sets were differentially expressed between MCPyV-negative and -positive MCC, with significant differential expression defined as at least 2-fold change in either direction and p-value of ≤ 0.05.,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+ T lymphocytes surrounding MCPyV-positive tumors.,In conclusion, our data suggest that loss of RB1 expression may play an important role in tumorigenesis of MCPyV-negative MCC.,Functional and clinical validation studies are needed to determine whether this tumor suppressor pathway represents an avenue for targeted therapy.
Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence.,The understanding of the molecular carcinogenesis of MCC is limited.,Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC.,Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples.,Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV).,Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT.,We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations.,Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent.,MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002.,This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.