Activation of Oncogenic and Immune-Response Pathways Is Linked to Disease-Specific Survival in Merkel Cell Carcinoma

SIMPLE SUMMARY: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Developing targeted therapies for MCC requires increased understanding of the mechanisms driving tumor progression. In this study, we aimed to identify genes, signaling pathways, and processes that play crucial roles in determining disease-specific survival in MCC. We analyzed the gene expression of 102 MCC tumors and identified genes that were upregulated among survivors and in patients who died from MCC. We cross-referenced these genes with online databases to identify the pathways and processes in which they function. Genes upregulated among survivors were mostly immune response related and genes upregulated among patients who died from MCC function in various pathways that promote cancer progression. These results could guide future studies investigating whether these genes and pathways could be used as prognostic markers, as markers to guide therapy selection, or as targets of precision therapy in MCC. ABSTRACT: Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin with a poor prognosis. Improving the prognosis of MCC by means of targeted therapies requires further understanding of the mechanisms that drive tumor progression. In this study, we aimed to identify the genes, processes, and pathways that play the most crucial roles in determining MCC outcomes. Methods: We investigated transcriptomes generated by RNA sequencing of formalin-fixed paraffin-embedded tissue samples of 102 MCC patients and identified the genes that were upregulated among survivors and in patients who died from MCC. We subsequently cross-referenced these genes with online databases to investigate the functions and pathways they represent. We further investigated differential gene expression based on viral status in patients who died from MCC. Results: We found several novel genes associated with MCC-specific survival. Genes upregulated in patients who died from MCC were most notably associated with angiogenesis and the PI3K-Akt and MAPK pathways; their expression predominantly had no association with viral status in patients who died from MCC. Genes upregulated among survivors were largely associated with antigen presentation and immune response. Conclusion: This outcome-based discrepancy in gene expression suggests that these pathways and processes likely play crucial roles in determining MCC outcomes.