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

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.

Transcriptomic analyses reveal three distinct molecular subgroups of Merkel cell carcinoma with differing prognoses

“…However, 3′ tag counting, which was used during RNA sequencing in our study, significantly improves specificity when examining differential gene expression of samples with low RIN 29 . Previously, we found a strong correlation between the logFC values of genes based on MCPyV status when comparing the transcriptomic data used in our study with transcriptomic data obtained from fresh frozen tissues provided by Harms et al (GSE39612), suggesting a high specificity of our transcriptomic data when studying differentially expressed genes, as compared with data from fresh frozen tissues 16,30 . Our findings could be further validated by studying an independent MCC cohort as well as validating RNA sequencing data using a different methodology, for example, quantitative PCR.…”

“…Harms et al (GSE39612), suggesting a high specificity of our transcriptomic data when studying differentially expressed genes, as compared with data from fresh frozen tissues. 16,30 Our findings could be further validated by studying an independent MCC cohort as well as validating RNA sequencing data using a different methodology, for example, quantitative PCR.…”

“…The extraction and sequencing of RNA and the processing of sequencing data were performed previously and are described in detail elsewhere 16 . Briefly, RNA extraction and sequencing were performed on FFPE primary tumor samples from 120 patients.…”

“…The extraction and sequencing of RNA and the processing of sequencing data were performed previously and are described in detail elsewhere. 16 Briefly, RNA extraction and sequencing were performed on FFPE primary tumor samples from 120 patients. Fourteen patients were excluded from the study since the corresponding samples did not pass the quality control during the processing of sequencing data.…”

Single-cell dissection of Merkel cell carcinoma heterogeneity unveils transcriptomic plasticity and therapeutic vulnerabilities

“…While there are limited whole transcriptomic studies utilizing MCC patient tumors at the single-cell and bulk RNA-seq levels, we identified a recent study with the largest published cohort of MCC patient tumors to date. 42 In the study, bulk RNA-seq was performed on 102 archival MCC tumors, and gene expression was correlated with clinical data, resulting in the identification of key marker genes associated with patient survival and death. These signatures, referred to as survival-associated genes (SAGs) and death-associated genes (DAGs), pointed toward an enrichment of oncogenic and immune-response pathways in conferring survival to MCC patients.…”