Abstract

Background: Merkel cell carcinoma (MCC) is a rare malignant neoplasm of the skin of neuroendocrine origin. Recent studies found that chromosomal abnormalities have been found in larger size tumors and in metastases. However, there are few studies in the literature investigating the epigenetic pathways involved in metastasis. Herein, we aim to explore the epigenetic pathways involved in metastasis using whole genome methylation. Methods: 24 patients (5 patients with matched primary and metastatic MCC, 10 patients with isolated primary MCC, 9 patients with metastatic MCC) were included. DNA was extracted from FFPE blocks & whole-genome methylation analysis was performed, interrogating 866,562 CpG sites with subsequent differential methylation analysis (DMP). The analysis was performed using the Minfi R package with a clinically validated pipeline after appropriate quality control. Results: Unsupervised clustering analysis identified two epigenetically separate clusters encompassing both primary and metastatic tumors based on gender. Neither site of the metastasis nor age appeared to affect clustering. Pathway analysis identified significant enrichment of HIF1 and ERB signaling pathways in both matched samples and the whole cohort (P =0.006, p=0.003). Focused DMP analysis of tumor suppressor genes and epigenetic modifiers did not show a significant difference in promoter hypomethylation in these genes in between metastatic and primary tumors. Conclusions: Both primary and metastatic MCC appears to be different epigenetically in males compared to females. Major hypoxia (HIF1a) and epidermal growth factor receptor (Erb), which are known to facilitate angiogenesis and metastatic phenotypes, seem to play a role in MCC. Silencing of key tumor suppressor genes does not play a significant role. Further validation of these preliminary findings in a larger cohort and by orthogonal methods (Immunohistochemical studies) is warranted.

Financial Disclosure:
No current or relevant financial relationships exist.