Frequent Detection of Merkel Cell Polyomavirus in Human Merkel Cell Carcinomas and Identification of a Unique Deletion in the VP1 Gene

Abstract

Merkel cell carcinoma (MCC) is a rare but very aggressive human malignancy of the elderly or immunosuppressed patients. Recently, the clonal integration of a new human polyoma virus, which was termed Merkel cell polyomavirus (MCPyV), has been reported in 8 of 10 MCC patients. In the present study, we studied the formalin-fixed and paraffinembedded tissue specimens of 39 MCC for the presence of MCPyV by PCR. We applied four different primer sets directed against the large T antigen and the VP1 gene of MCPyV. We were able to detect MCPyV in 77% (n = 30) of MCC as confirmed by sequence analyses of the PCR products. Sequence analyses showed only minor nucleotide changes compared with the previously published MCC sequences. In addition, one patient revealed the amplification of two PCR products using PCR primers directed against the VP1 gene. Sequence analyses confirmed the presence of the expected 351-bp PCR product and in addition a second PCR product of 261 bp containing a unique 90-bp deletion in the VP1 gene, which will lead to a predicted loss of 28 amino acids. The unique 90-bp deletion within the VP1 gene possibly is a result of incomplete viral integration of MCPyV in the MCC. The presence of MCPyV in the majority of MCC tissue specimens in our study strongly underlines a possible role for MCPyV as an etiologic agent in the carcinogenesis of MCC. [Cancer Res 2008;68(13):5009-13]

Chronic lymphocytic leukaemia patients have a high risk of Merkel-cell polyomavirus DNA-positive Merkel-cell carcinoma

“…The link between immunosuppression and MCC may be MCPyV infection (Feng et al, 2008), although conclusive evidence for a causative role of MCPyV for MCC is still lacking. We recently detected MCPyV DNA in 79.8% of 114 MCCs diagnosed in Finland (Sihto et al, 2009), which is a slightly larger proportion than 72.3% detected in five smaller studies that included a total of 148 MCCs (Feng et al, 2008;Foulongne et al, 2008;Garneski et al, 2008;Kassem et al, 2008;Becker et al, 2009;Sihto et al, 2009). Despite the small numbers, the current finding of presence of MCPyV DNA in all MCCs among the patients who were also diagnosed with CLL suggests a role for MCPyV infection in the molecular pathogenesis of MCC in immunocompromised patients.…”

Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma

“…The fact that three different laboratories have detected Merkel cell polyomavirus genomic sequences in tumor DNA in 75-80% of Merkel cell carcinoma specimens, 10,11 together with the demonstration that viral DNA is clonally distributed in Merkel cell carcinoma 10,11 and is present in primary tumors as well as paired metastases, 10 provides evidence that Merkel cell polyomavirus has a function in Merkel cell carcinoma oncogenesis. Although a formal etiological link has not been established, in the single Merkel cell carcinoma to date in which the genomic site of integration of Merkel cell polyomavirus has been evaluated, the virus is apparently inserted within the human receptor tyrosine phosphatase gene at 3p14.2, a finding that suggests that oncogenesis may occur via insertional mutagenesis as well as T-antigen expression.…”

“…9 Merkel cell carcinoma was recently shown to harbor a novel polyomavirus aptly named the Merkel cell polyomavirus, in the majority of cases. 10,11 The virus is a nonenveloped, doublestranded DNA virus with a 5387 bp circular genome that shares a high degree of homology with African green monkey polyomavirus viral proteins and T-cell antigens. In common with other polyomaviruses that infect humans (including BK virus, JC virus, KI virus, and WU virus), Merkel cell polyomavirus expresses a large T-cell antigen.…”

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

“…Using digital transcriptome subtraction, we recently identified Merkel cell polyomavirus (MCV) as a novel polyomavirus integrated into the genome of MCC tumors (3,4). The close association between MCV and MCC has been confirmed by others (5). Polyomaviruses are small circular DNA viruses encoding a T antigen oncoprotein locus.…”