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

Kassem, Ahmad; Schöpflin, Anja; Díaz, Carlos Guerrero; Weyers, Wolfgang; Stickeler, Elmar; Werner, Martin; Hausen, Axel zur

doi:10.1158/0008-5472.can-08-0949

Cited by 331 publications

(331 citation statements)

References 22 publications

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“…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.…”

Section: Discussionmentioning

confidence: 54%

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

et al. 2009

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BACKGROUND: Immunosuppression and Merkel-cell polyomavirus (MCPyV) infection may have a role in the pathogenesis of Merkelcell carcinoma (MCC), a rare neuroendocrine carcinoma of the skin. METHODS: We studied incidence of chronic lymphocytic leukaemia (CLL) and MCC from the files of the Finnish Cancer Registry and the largest hospital of Finland, Helsinki University Central Hospital, from 1979 to 2006. Presence of MCPyV DNA in MCCs was investigated by quantitative PCR. RESULTS: We identified 4164 patients diagnosed with CLL and 172 diagnosed with MCC. Six patients diagnosed with both diseases were found; CLL was the first diagnosis in four cases and MCC in two. The standardised incidence ratio (SIR) for CLL after the diagnosis of MCC was highly elevated, 17.9 (95% confidence interval (CI), 2.2 -64.6; Po0.001), and the SIR for MCC after the diagnosis of CLL was also elevated, 15.7 (3.2 -46.0, Po0.01). Merkel-cell polyomavirus DNA was present in all five MCCs with tumour tissue available for analysis. CONCLUSIONS: We conclude that patients diagnosed with CLL have a substantially increased risk for MCC, and vice versa. Merkel-cell polyomavirus DNA is frequently present in MCCs that occur in CLL patients. Immunosuppression related with CLL and viral infection might explain the association between CLL and MCC.

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Section: Discussionmentioning

confidence: 54%

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

et al. 2009

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma

2009

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It has recently been shown that Merkel cell carcinoma, a rare and often lethal cutaneous malignancy, frequently harbors a novel clonally integrated polyomavirus aptly named Merkel cell polyomavirus. We aimed to study the prevalence of Merkel cell polyomavirus in cases of Merkel cell carcinoma, using specimens from formalin-fixed, paraffin-embedded tissue blocks. In our archives we identified 41 cases of Merkel cell carcinoma (from 29 different patients). Of these, 20 cases were primary cutaneous tumors, 4 were local recurrences, and 17 were metastases. PCR using two previously published primer sets, LT1 (440 bp amplicon) and LT3 (308 bp amplicon), as well as a novel primer set MCVPS1 (109 bp amplicon), was performed on all cases. Selected PCR products were sequenced to confirm amplicon identity. In addition, the MCVPS1 products were digested with BamH1, yielding an 83 bp product. Amplifiable DNA was recovered in all 41 study cases. The detection rate of Merkel cell polyomavirus for each of the three primer sets was 22 of 29 patients (76%) for MCVPS1, 12 of 29 (41%) for LT3, and 8 of 29 (28%) for LT1. The variation between primer set detection rates was largely due to poor DNA quality, as supported by poor amplification of the higher molecular weight markers in size control ladder products and the fact that all cases that were positive by LT1 and LT3 were positive by MCVPS1. Our findings provide further evidence to link Merkel cell polyomavirus with a possible role in the oncogenesis of Merkel cell carcinoma. On a more practical level, our paraffin-optimized primer set may be used as an ancillary test to confirm the diagnosis of Merkel cell carcinoma in the clinical setting or for screening other rare tumor types for the causative virus, especially those tumor types that are underrepresented in frozen tissue repositories.

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“…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.…”

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confidence: 96%

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

Shuda

Feng

Kwun

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

632

908

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Merkel cell polyomavirus (MCV) is a virus discovered in our laboMerkel cell carcinoma ͉ pRB interaction ͉ viral integration ͉ virus replication ͉ helicase M erkel cell carcinoma (MCC) is an aggressive skin cancer associated with sun exposure and immunosuppression (1, 2). 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. T antigens are expressed from variably spliced viral transcripts that target tumor suppressor and cell cycle regulatory proteins, including retinoblastoma tumor suppressor protein (Rb) (6), p53 (7, 8), protein phosphatase 2A (9), and Bub1 (10). Murine polyomavirus (MuPyV) middle T (MT) antigen, a membrane-bound protein, is particularly potent in initiating cell transformation through interactions with phosphatidylinositol 3-kinase, protein phosphatase 2A, Src, and Shc proteins (11,12). MCV large T (LT) antigen retains conserved domains, such as pocket Rb binding LXCXE and DnaJ motifs, present across virus species (13). LT not only encodes tumor suppressor targeting domains but also origin binding and helicase/ATPase functions required for viral genome replication. MCV integration in MCC tumors is incompatible with transmissible virus and likely represents a rare biological accident in which the tumor cell is a dead-end host. The monoclonal pattern of MCV integration into MCC tumors suggests that virus integration occurs before tumor cell expansion and that MCV is a contributing factor in a portion of MCC (3).We have isolated MCV T antigen sequences from both tumor cases and nontumor cases to characterize their abilities to act as a viral DNA replicase. Sequence analysis demonstrates that LT protein is prematurely truncated in all MCC cases, whereas the Rb-interacting domain is preserved. Viruses from nontumor sources do not possess these mutations. We also describe here an MCC cell line stably harboring MCV and an origin replication assay to assess MCV replication. We show that wild type (WT) LT from nontumorous sources activates MCV replication of integrated tumor virus, suggesting that MCV-associated MCC arises from a two-step process in which viral genome integrates into the host genome and develops T antigen mutations to prevent autonomous viral genome replication. Failure to truncate the viral T antigen may lead to DNA damage responses or immune recognition that hinders nascent tumor cell survival.

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

Cited by 331 publications

References 22 publications

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

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

Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma

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

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