Abstract Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer, most often driven by integration of Merkel cell polyomavirus (MCPyV). While anti‐PD‐1/PD‐L1 therapies have improved outcomes, reliable prognostic biomarkers remain limited. Tripartite motif‐containing protein 25 (TRIM25), a critical activator of innate immunity, was evaluated here for its clinical and biological relevance in MCC. We analysed TRIM25 mRNA and protein expression in 102 MCC cases and 9 MCC cell lines, respectively, and assessed associations with MCPyV status, clinicopathological characteristics and patient survival. Differential gene expression analysis was performed to identify pathways associated with TRIM25 expression in both low and high TRIM25 ‐expressing tumour groups. High TRIM25 expression was significantly associated with MCPyV positivity in both patient tumours ( p = .004) and cell lines ( p = .016), and TRIM25 and MCPyV mRNA levels correlated positively in tumours ( r = 0.264, p = .013). Patients with low TRIM25 expression had a significantly poorer 5‐year disease‐specific survival than those with high expression (53% vs. 78%, p = .013). Notably, Cox multivariate analysis confirmed that TRIM25 serves as an independent prognostic marker, irrespective of MCPyV status. Pathway analysis revealed that low TRIM25 expression was linked to antigen presentation pathways, while high TRIM25 expression was associated with cell cycle regulation. Our findings suggest that TRIM25 serves as a valuable prognostic biomarker in MCC. Additionally, TRIM25 may play a pathogenic role in MCPyV‐positive tumours, warranting further investigation to elucidate its mechanistic involvement in MCC tumourigenesis.
Fagerstedt et al. (Sat,) studied this question.