Abstract
Merkel Cell Polyomavirus (MCPyV) is associated with Merkel Cell carcinoma (MCC), a rare, aggressive skin cancer with neuroendocrine features. The causal role of MCPyV is highly suggested by monoclonal integration of its genome and expression of the viral large T (LT) antigen in MCC cells. We investigated and characterized MCPyV molecular features in MCC, respiratory, urine and blood samples from 33 patients by quantitative PCR, sequencing and detection of integrated viral DNA. We examined associations between either MCPyV viral load in primary MCC or MCPyV DNAemia and survival. Results were interpreted with respect to the viral molecular signature in each compartment. Patients with MCC containing more than 1 viral genome copy per cell had a longer period in complete remission than patients with less than 1 copy per cell (34 vs 10 months, P = 0.037). Peripheral blood mononuclear cells (PBMC) contained MCPyV more frequently in patients sampled with disease than in patients in complete remission (60% vs 11%, P = 0.00083). Moreover, the detection of MCPyV in at least one PBMC sample during follow-up was associated with a shorter overall survival (P = 0.003). Sequencing of viral DNA from MCC and non MCC samples characterized common single nucleotide polymorphisms defining 8 patient specific strains. However, specific molecular signatures truncating MCPyV LT were observed in 8/12 MCC cases but not in respiratory and urinary samples from 15 patients. New integration sites were identified in 4 MCC cases. Finally, mutated-integrated forms of MCPyV were detected in PBMC of two patients with disseminated MCC disease, indicating circulation of metastatic cells. We conclude that MCPyV molecular features in primary MCC tumour and PBMC may help to predict the course of the disease.
Highlights
Polyomaviruses are small, non enveloped double stranded DNA viruses which infect many species with a restricted host range
Merkel cell polyomavirus (MCPyV) is a recently discovered virus highly associated with a rare skin cancer, Merkel cell carcinoma (MCC)
The causal role of Merkel Cell Polyomavirus (MCPyV) in cancer is suggested by integration of viral sequences into the cell genome and by a specific molecular signature
Summary
Polyomaviruses are small, non enveloped double stranded DNA viruses which infect many species with a restricted host range. Polyomaviruses persist latently in the host and may reactivate, causing disease in the immunocompromised [4,5], but have not been firmly associated with cancer in humans [6]. MCPyV present in MCC tissue exhibited a molecular signature, consisting of mutations which truncate LT and suppress its helicase domain required for viral replication [9]. These features are similar to molecular defects observed in MPyV [10] and bring strong evidence for a causative role of the virus in MCC
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