Abstract 1999: Defining the distinct molecular landscapes of primary tumors and metastases in Merkel cell carcinoma

Abstract Merkel cell carcinoma (MCC) is an aggressive skin cancer characterized by high metastatic potential and poor survival rates. Identifying biomarkers for early detection of metastatic MCC is crucial for improving clinical outcomes. In this study, we analyzed bulk RNA-sequencing data from the GEO dataset GSE235092, identifying 481 differentially expressed genes (DEGs) between primary tumors (n=43) and metastases (n=28) (fold change >2, adjusted p <0.01). Among these, 66 genes were upregulated and 415 were downregulated in metastases. Downregulated DEGs were enriched in processes and pathways associated with metastasis, such as cell-cell adhesion, focal adhesion, and epithelial-mesenchymal transition. To further investigate, we performed pseudobulk differential expression analysis on tumor cells from primary (n=13) and metastasis tumors (n=10) using single-cell RNA-sequencing (scRNA-seq) data (GSE235090). This analysis revealed 43 DEGs (fold change >1.5, adjusted p <0.05), with 3 overlapping with the bulk RNA-seq findings. Subsequent subdivision of scRNA-seq metastasis samples into regional and distant metastases identified 6 DEGs specific to regional metastases compared to primary tumors, 5 to distant metastases, and 1 common to both. Validation of these DEG candidates in our MCC cohort of 102 primary tumors, based on RNA sequencing, identified SLC4A7, CPVL, ENG, MYLIP, and MXRA8 as strong candidates linked to tumor metastasis, survival outcome, Merkel cell polyomavirus (MCPyV) status and other clinical characteristics. Additionally, scRNA-seq analysis highlighted distinct tumor microenvironment compositions among primary tumors, regional metastases, and distant metastases. Considering the role of MCPyV in MCC progression, we examined DEGs between primary and metastasis under MCPyV-positive and MCPyV-negative statuses using bulk RNA data. Gene set enrichment analysis uncovered 55 MYC-targeted genes and 52 E2F-targeted genes that were suppressed in MCPyV-positive patients but activated in MCPyV-negative patients. These findings provide new insights into MCC metastasis and highlight potential biomarkers for tumor progression and targeted therapies. Citation Format: Yajie Yang, Sami Kilpinen, Harri Sihto, Libuse Janská, Xiaohao Wang, Catharina Larsson, Weng-Onn Lui. Defining the distinct molecular landscapes of primary tumors and metastases in Merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1999.