Abstract
A human polyomavirus was recently discovered in Merkel cell carcinoma (MCC) specimens. The Merkel cell polyomavirus (MCPyV) genome undergoes clonal integration into the host cell chromosomes of MCC tumors and expresses small T antigen and truncated large T antigen. Previous studies have consistently reported that MCPyV can be detected in approximately 80% of all MCC tumors. We sought to increase the sensitivity of detection of MCPyV in MCC by developing antibodies capable of detecting large T antigen by immunohistochemistry. In addition, we expanded the repertoire of quantitative PCR primers specific for MCPyV to improve the detection of viral DNA in MCC. Here we report that a novel monoclonal antibody detected MCPyV large T antigen expression in 56 of 58 (97%) unique MCC tumors. PCR analysis specifically detected viral DNA in all 60 unique MCC tumors tested. We also detected inactivating point substitution mutations of TP53 in the two MCC specimens that lacked large T antigen expression and in only 1 of 56 tumors positive for large T antigen. These results indicate that MCPyV is present in MCC tumors more frequently than previously reported and that mutations in TP53 tend to occur in MCC tumors that fail to express MCPyV large T antigen.
Highlights
Merkel cell carcinoma (MCC) is a rare skin cancer with high risk for metastasis and death [1]
FFPE specimens corresponding to 60 patients presenting with MCC to a referral specialty clinic were included in this study (Supplemental Table 1; supplemental material available online with this article; doi:10.1172/JCI64116DS1)
A total of 75 archival MCC samples were available for study that included 44 primary cutaneous, meta static lymph node, and 6 metastatic visceral tumors obtained at initial presentation and recurrent tumors obtained after ini tial therapy (Supplemental Table 1)
Summary
Merkel cell carcinoma (MCC) is a rare skin cancer with high risk for metastasis and death [1]. Recognition of the increased risk for developing MCC in immu nocompromised patients led to a search for a pathogenic cause and the discovery of the Merkel cell polyomavirus (MCPyV). Sequencing of RNA from 4 MCC specimens revealed a novel tran script distantly related to large T antigen of the polyomavirus fam ily [10]. Sequencing of the complete MCPyV genome revealed that it had features typical of a polyomavirus, including a circular dou ble-stranded DNA genome of 5,387 bp; an early region encoding genes for large and small T antigens; a late region with genes for the viral coat proteins VP1, VP2, and VP3; and a regulatory region that contained the viral origin of replication and a bidirectional promoter for the early and late genes
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