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

Area of Science:

• Oncology
• Genomics
• Dermatology

Background:

• Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with an uncertain cell of origin.
• Proposed origins include hair follicle stem cells, interfollicular epidermis, dermal stem cells, or immune cells.
• MCC's heterogeneity suggests it may arise from multiple cell types or represent distinct carcinoma entities.

Purpose of the Study:

• To investigate the molecular heterogeneity of MCC.
• To identify gene expression patterns linked to clinical relevance or cell of origin.
• To uncover distinct molecular subgroups within MCC.

Main Methods:

• RNA sequencing was performed on 102 primary MCC tumor samples.
• The top 200 most variably expressed genes were identified and analyzed.
• Hierarchical clustering of genes and tumors was used to identify expression patterns.

Main Results:

• Three distinct molecular subgroups of MCC with prognostic relevance were identified.
• Merkel cell polyomavirus (MCPyV)-negative tumors showed high embryonic development gene expression and low neuroendocrine gene expression compared to MCPyV-positive tumors.
• Two prognostically relevant subgroups within MCPyV-positive MCC were distinguished by epidermal gene expression patterns.

Conclusions:

• MCC displays significant molecular heterogeneity, supporting the concept of multiple origins.
• Distinct molecular subgroups, particularly in MCPyV-positive MCC, have prognostic implications.
• The differential expression of epidermis-related genes suggests both epidermal and non-epidermal origins for MCC.