This study investigates the role of Merkel cell polyomavirus (MCV) in the development of Merkel cell carcinoma (MCC), a rare and aggressive form of skin cancer. The authors used digital transcriptome subtraction (DTS) to detect a fusion transcript between MCV T antigen and a human receptor tyrosine phosphatase, leading to the identification and sequencing of the MCV genome. MCV sequences were found in 80% of MCC tumors but only in 8% of control tissues, suggesting a potential link to MCC. Further analysis revealed that MCV DNA was integrated into the tumor genome in a clonal pattern, indicating that MCV infection and integration occurred before the clonal expansion of tumor cells. This finding supports the hypothesis that MCV may contribute to the pathogenesis of MCC. The study also highlights the utility of DTS in discovering cryptic human viruses and its limitations in detecting low-abundance viruses.This study investigates the role of Merkel cell polyomavirus (MCV) in the development of Merkel cell carcinoma (MCC), a rare and aggressive form of skin cancer. The authors used digital transcriptome subtraction (DTS) to detect a fusion transcript between MCV T antigen and a human receptor tyrosine phosphatase, leading to the identification and sequencing of the MCV genome. MCV sequences were found in 80% of MCC tumors but only in 8% of control tissues, suggesting a potential link to MCC. Further analysis revealed that MCV DNA was integrated into the tumor genome in a clonal pattern, indicating that MCV infection and integration occurred before the clonal expansion of tumor cells. This finding supports the hypothesis that MCV may contribute to the pathogenesis of MCC. The study also highlights the utility of DTS in discovering cryptic human viruses and its limitations in detecting low-abundance viruses.