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Merkel Cell Polyomavirus

The Merkel cell polyomavirus (MCPyV) was identified in humans in 2008. This virus is suspected to be involved in most, but not all, cases of Merkel Cell Carcinoma, a relatively rare type of skin cancer.

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Recent Research Publications About MCPyV and Cancer

Kim GJ, Lee JH, Lee DH
Clinical and prognostic significance of Merkel cell polyomavirus in nonsmall cell lung cancer.
Medicine (Baltimore). 2017; 96(3):e5413 [PubMed] Free Access to Full Article Related Publications
Recently, an association between Merkel cell polyomavirus (MCPyV) and epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) was reported. However, the underlying carcinogenic effects and the prognosis related to MCPyV are still unclear. The aim of this study was to clarify the incidence and prognosis related to MCPyV infections in NSCLC.Tissue samples from 167 NSCLC patients (92 with squamous cell carcinomas [SCCs] and 75 with adenocarcinomas) were analyzed for the presence of MCPyV and EGFR mutations. Clinicopathological characteristics, disease-free survival rate, and overall survival rate were assessed with respect to MCPyV.MCPyV DNA was detected in 30 patients (18.0%) out of 167 patients, and EGFR mutations were found in 31 out of 127 patients (24.4%). EGFR mutations were more frequently detected in MCPyV-positive patients than in MCPyV-negative patients; however, this did not reach statistical significance (P = 0.075). There was no difference in overall survival between patients with and without MCPyV infections. The disease-free survival rate of patients with pN0 stage, SCC, or EGFR mutations was lower for patients with MCPyV than without MCPyV (P = 0.036, 0.042, and 0.050, respectively).Although the prevalence of MCPyV infection was relatively low, the presence of MCPyV DNA was significantly correlated with cancer prognosis in subgroups of NSCLC patients. These results suggest that MCPyV may be partly associated with pathogenesis and prognosis in some cases of NSCLC.

Falchook GS, Rady P, Konopinski JC, et al.
Merkel cell polyomavirus and human papilloma virus in proliferative skin lesions arising in patients treated with BRAF inhibitors.
Arch Dermatol Res. 2016; 308(5):357-65 [PubMed] Related Publications
The potential role of oncogenic viruses mediating development of proliferative skin lesions in patients treated with RAF inhibitors is poorly understood. The objective of this study was to investigate human papilloma virus (HPV) and Merkel cell polyomavirus (MCPyV) in skin lesions among patients treated with RAF inhibitors with the help of a case series describing prevalence of HPV, MCPyV, and RAS mutations in skin biopsies obtained from patients receiving RAF inhibitors and developing cutaneous lesions. HPV-DNA was amplified by PCR utilizing multiple nested primer systems designed for detection of a broad range of HPV types. MCPyV copy number determination with real time PCR technology was performed by a "Quantification of MCPyV, small t region" kit. Thirty-six patients were tested (squamous cell carcinoma (SCC) = 14; verruca vulgaris = 15; other = 11). Nine of 12 SCCs (75 %) and eight of 13 verruca vulgaris lesions (62 %) tested positive for MCPyV whereas none of the normal skin biopsies obtained from nine of these patients tested positive for MCPyV (p = 0.0007). HPV incidence in cutaneous SCCs was not different compared to normal skin (50 vs. 56 %, p = 0.86). The association between MCPyV and proliferative skin lesions after RAF inhibitor therapy merits further investigation.

Urso C, Pierucci F, Sollai M, et al.
Detection of Merkel cell polyomavirus and human papillomavirus DNA in porocarcinoma.
J Clin Virol. 2016; 78:71-3 [PubMed] Related Publications
BACKGROUND: Increasing evidences support the role of Merkel cell polyomavirus (MCPyV) and human papillomavirus (HPV) in non-cutaneous and cutaneous tumours. Porocarcinoma is a rare malignant neoplasm that arises from the intraepidermal ductal portion of the eccrine sweat glands. The aetiology of porocarcinoma is largely unknown and no systematic studies have been done to investigate the implication of infectious agents in the pathogenesis of this tumour.
OBJECTIVES: To investigate the possible association between MCPyV and/or HPV infection and porocarcinoma.
STUDY DESIGN: Forty-four formalin-fixed paraffin-embedded (FFPE) porocarcinomas (40 primary and 4 metastatic) and 10 healthy skin specimens (controls), were analysed for the presence of MCPyV and HPV DNA using molecular detection methods.
RESULTS: MCPyV DNA was found in 27/40 (68%) primary porocarcinomas and in 3/10 (30%) controls (Fisher exact test: p<0.04). No significant difference in viral load was observed between tumours and healthy skin. Moreover, 2/40 primary porocarcinomas tested positive for high-risk HPV16. Cutaneous beta-HPV infection was detected in 16/40 (40%) porocarcinomas and in 6/10 (60%) controls. No particular beta-HPV types were significantly associated with tumour or with healthy skin. Two out of 4 metastatic biopsies were MCPyV DNA positive. All metastatic samples had mixed infections with cutaneous HPV types.
CONCLUSIONS: This study demonstrated a significantly high prevalence of MCPyV and the presence of a broad spectrum of HPV types in porocarcinoma and provided the first available data about viral infections in this tumour. To understand the role, if any, of viral infections in the pathogenesis of porocarcinoma further studies are needed.

Gossai A, Waterboer T, Nelson HH, et al.
Prospective Study of Human Polyomaviruses and Risk of Cutaneous Squamous Cell Carcinoma in the United States.
Cancer Epidemiol Biomarkers Prev. 2016; 25(5):736-44 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Merkel cell polyomavirus (PyV) is causally related to Merkel cell carcinoma, a rare skin malignancy. Little is known about the serostability of other PyVs over time or associations with cutaneous squamous cell carcinoma (SCC).
METHODS: As part of a U.S. nested case-control study, antibody response against the PyV VP1 capsid proteins of BK and John Cunningham virus (JC) was measured using multiplex serology on 113 SCC cases and 229 gender, age, and study center-matched controls who had a prior keratinocyte cancer. Repeated serum samples from controls and both pre and postdiagnosis samples from a subset of SCC cases were also tested. Odds ratios (OR) for SCC associated with seropositivity to each PyV type were estimated using conditional logistic regression.
RESULTS: Among controls, BK and JC seroreactivity was stable over time, with intraclass correlation coefficients of 0.86 for BK and 0.94 for JC. Among cases, there was little evidence of seroconversion following SCC diagnosis. JC seropositivity prior to diagnosis was associated with an elevated risk of SCC (OR = 2.54; 95% CI, 1.23-5.25), and SCC risk increased with increasing quartiles of JC (Ptrend = 0.004) and BK (Ptrend = 0.02) seroreactivity.
CONCLUSIONS: PyV antibody levels were stable over time and following an SCC diagnosis. A history of PyV infection may be involved in the occurrence of SCC in a population at high risk for this malignancy.
IMPACT: A single measure of PyV seroreactivity appears a reliable indicator of long-term antibody status, and PyV exposure may be a risk factor for subsequent SCC. Cancer Epidemiol Biomarkers Prev; 25(5); 736-44. ©2016 AACR.

Wu JH, Simonette RA, Nguyen HP, et al.
Emerging differential roles of the pRb tumor suppressor in trichodysplasia spinulosa-associated polyomavirus and Merkel cell polyomavirus pathogeneses.
J Clin Virol. 2016; 76:40-3 [PubMed] Related Publications
BACKGROUND: Merkel cell carcinoma (MCC) and trichodysplasia spinulosa (TS) are two proliferative cutaneous diseases caused by the Merkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa-associated polyomavirus (TSPyV) respectively. Recently, studies have elucidated a key role of the small tumor (sT) antigen in the proliferative pathogenic mechanisms of MCPyV and likely TSPyV. While both sT antigens have demonstrated a capacity in regulating cellular pathways, it remains unknown whether MCPyV and TSPyV sT antigens contribute similarly or differentially to cell proliferation.
OBJECTIVES: The present study aims to explore the proliferative potential of MCPyV and TSPyV sT antigens by investigating their regulatory effects on the retinoblastoma protein (pRb) tumor suppressor.
STUDY DESIGN: Inducible cell lines expressing MCPyV sT or TSPyV sT were created using a lentiviral packaging system. Cellular proteins were extracted and subjected to SDS-PAGE followed by Western blot detection and densitometric analysis.
RESULTS: Expression of TSPyV sT markedly enhanced the phosphorylation of pRb in Western blot experiments. In contrast, expression of MCPyV sT did not alter pRb phosphorylation under the same experimental conditions. Densitometric analysis revealed that TSPyV sT antigen expression nearly doubled the ratio of phosphorylated to total pRb (P<0.001, Student's T-test), while MCPyV sT antigen expression did not cause significant change in pRb phosphorylation status.
CONCLUSION: Given that hyperphosphorylation of pRb is associated with dysregulation of the cell cycle, S-phase induction, and increased cell proliferation, our findings support an important role of TSPyV-mediated pRb deactivation in the development of TS. The observation that the pRb tumor suppressor is inactivated by TSPyV sT but not MCPyV sT provides further insights into the distinct pathobiological mechanisms of MCC and TS.

Veija T, Sarhadi VK, Koljonen V, et al.
Hotspot mutations in polyomavirus positive and negative Merkel cell carcinomas.
Cancer Genet. 2016 Jan-Feb; 209(1-2):30-5 [PubMed] Related Publications
Merkel cell polyomavirus (MCV) infection underlies most Merkel cell carcinoma (MCC), a primary neuroendocrine carcinoma of the skin. While previous research has focused on MCV-positive MCC tumors, less is known about the oncogenesis in MCV-negative tumors. In this study, we analyzed mutational status of 27 MCC tumors with known MCV status for hotspot regions of 50 cancer-related genes by targeted next-generation sequencing using the Ion AmpliSeq Cancer Hotspot Panel. In addition to previously reported TP53, KIT, and PIK3CA gene mutations, we found somatic mutations in the tyrosine kinase domain of the EGFR gene in a small proportion of the cells in six tumor tissues. RB1 mutations were seen only in virus negative tumors. Hotspot mutations were more frequent in MCV-negative tumors, although the difference was not statistically significant. No clear hotspot mutation profile was observed. Novel RB1 mutations were detected only in MCV-negative tumors.

Miles BA, Goldenberg D,
Merkel cell carcinoma: Do you know your guidelines?
Head Neck. 2016; 38(5):647-52 [PubMed] Related Publications
BACKGROUND: Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine malignancy that exhibits clinically aggressive features and is associated with a poor prognosis. The incidence of MCC seems to be increasing for reasons unknown, and is estimated to be 0.32/100,000 in the United States.
METHODS: This article will review the current literature and National Comprehensive Cancer Network practice guidelines in the treatment of MCC.
RESULTS: Resection of MCC with negative margins remains the mainstay of therapy. Positive nodal disease should be treated with neck dissection and adjuvant radiotherapy. High-risk patients should undergo adjuvant radiotherapy, which improves oncologic outcomes. The role of chemotherapy is less clear and is currently reserved for advanced-stage MCC and palliative therapy.
CONCLUSION: The pathogenesis of MCC has recently been impacted with the discovery of the Merkel cell polyomavirus (MCPyV). Research to establish targeted and immunologic therapeutic options are ongoing.

Goh G, Walradt T, Markarov V, et al.
Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.
Oncotarget. 2016; 7(3):3403-15 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

Shuda M, Guastafierro A, Geng X, et al.
Merkel Cell Polyomavirus Small T Antigen Induces Cancer and Embryonic Merkel Cell Proliferation in a Transgenic Mouse Model.
PLoS One. 2015; 10(11):e0142329 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Merkel cell polyomavirus (MCV) causes the majority of human Merkel cell carcinomas (MCC) and encodes a small T (sT) antigen that transforms immortalized rodent fibroblasts in vitro. To develop a mouse model for MCV sT-induced carcinogenesis, we generated transgenic mice with a flox-stop-flox MCV sT sequence homologously recombined at the ROSA locus (ROSAsT), allowing Cre-mediated, conditional MCV sT expression. Standard tamoxifen (TMX) administration to adult UbcCreERT2; ROSAsT mice, in which Cre is ubiquitously expressed, resulted in MCV sT expression in multiple organs that was uniformly lethal within 5 days. Conversely, most adult UbcCreERT2; ROSAsT mice survived low-dose tamoxifen administration but developed ear lobe dermal hyperkeratosis and hypergranulosis. Simultaneous MCV sT expression and conditional homozygous p53 deletion generated multi-focal, poorly-differentiated, highly anaplastic tumors in the spleens and livers of mice after 60 days of TMX treatment. Mouse embryonic fibroblasts from these mice induced to express MCV sT exhibited anchorage-independent cell growth. To examine Merkel cell pathology, MCV sT expression was also induced during mid-embryogenesis in Merkel cells of Atoh1CreERT2/+; ROSAsT mice, which lead to significantly increased Merkel cell numbers in touch domes at late embryonic ages that normalized postnatally. Tamoxifen administration to adult Atoh1CreERT2/+; ROSAsT and Atoh1CreERT2/+; ROSAsT; p53flox/flox mice had no effects on Merkel cell numbers and did not induce tumor formation. Taken together, these results show that MCV sT stimulates progenitor Merkel cell proliferation in embryonic mice and is a bona fide viral oncoprotein that induces full cancer cell transformation in the p53-null setting.

Grundhoff A, Fischer N
Merkel cell polyomavirus, a highly prevalent virus with tumorigenic potential.
Curr Opin Virol. 2015; 14:129-37 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV) is the only human polyomavirus known to be involved in tumorigenesis. Like other human polyomaviruses, MCPyV is highly prevalent in the healthy population, yet the MCPyV-associated Merkel cell carcinoma (MCC) is a very rare disease. Although in vitro and in vivo models have provided significant details regarding molecular functions of viral oncoproteins during cellular transformation, many open questions about the natural life cycle of the virus, its mechanisms of persistence and the precise role of MCPyV during MCC pathogenesis remain. This review will carve out the specifics of MCPyV biology and discuss unresolved issues to help the reader gain a better understanding of what may differentiate MCPyV from other polyomaviruses.

Schrama D, Hesbacher S, Angermeyer S, et al.
Serine 220 phosphorylation of the Merkel cell polyomavirus large T antigen crucially supports growth of Merkel cell carcinoma cells.
Int J Cancer. 2016; 138(5):1153-62 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV) is regarded as a major causal factor for Merkel cell carcinoma (MCC). Indeed, tumor cell growth of MCPyV-positive MCC cells is dependent on the expression of a truncated viral Large T antigen (LT) with an intact retinoblastoma protein (RB)-binding site. Here we determined the phosphorylation pattern of a truncated MCPyV-LT characteristically for MCC by mass spectrometry revealing MCPyV-LT as multi-phospho-protein phosphorylated at several serine and threonine residues. Remarkably, disruption of most of these phosphorylation sites did not affect its ability to rescue knockdown of endogenous T antigens in MCC cells indicating that phosphorylation of the respective amino acids is not essential for the growth promoting function of MCPyV-LT. However, alteration of serine 220 to alanine completely abolished the ability of MCPyV-LT to support proliferation of MCC cells. Conversely, mimicking the phosphorylated state by mutation of serine 220 to glutamic acid resulted in a fully functional LT. Moreover, MCPyV-LT(S220A) demonstrated reduced binding to RB in co-immunoprecipitation experiments as well as weaker induction of RB target genes in MCC cells. In conclusion, we provide evidence that phosphorylation of serine 220 is required for efficient RB inactivation in MCC and may therefore be a potential target for future therapeutic approaches.

Theiss JM, Günther T, Alawi M, et al.
A Comprehensive Analysis of Replicating Merkel Cell Polyomavirus Genomes Delineates the Viral Transcription Program and Suggests a Role for mcv-miR-M1 in Episomal Persistence.
PLoS Pathog. 2015; 11(7):e1004974 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Merkel cell polyomavirus (MCPyV) is considered the etiological agent of Merkel cell carcinoma and persists asymptomatically in the majority of its healthy hosts. Largely due to the lack of appropriate model systems, the mechanisms of viral replication and MCPyV persistence remain poorly understood. Using a semi-permissive replication system, we here report a comprehensive analysis of the role of the MCPyV-encoded microRNA (miRNA) mcv-miR-M1 during short and long-term replication of authentic MCPyV episomes. We demonstrate that cells harboring intact episomes express high levels of the viral miRNA, and that expression of mcv-miR-M1 limits DNA replication. Furthermore, we present RACE, RNA-seq and ChIP-seq studies which allow insight in the viral transcription program and mechanisms of miRNA expression. While our data suggest that mcv-miR-M1 can be expressed from canonical late strand transcripts, we also present evidence for the existence of an independent miRNA promoter that is embedded within early strand coding sequences. We also report that MCPyV genomes can establish episomal persistence in a small number of cells for several months, a time period during which viral DNA as well as LT-Ag and viral miRNA expression can be detected via western blotting, FISH, qPCR and southern blot analyses. Strikingly, despite enhanced replication in short term DNA replication assays, a mutant unable to express the viral miRNA was severely limited in its ability to establish long-term persistence. Our data suggest that MCPyV may have evolved strategies to enter a non- or low level vegetative stage of infection which could aid the virus in establishing and maintaining a lifelong persistence.

Batinica M, Akgül B, Silling S, et al.
Correlation of Merkel cell polyomavirus positivity with PDGFRα mutations and survivin expression in Merkel cell carcinoma.
J Dermatol Sci. 2015; 79(1):43-9 [PubMed] Related Publications
BACKGROUND: Merkel cell carcinoma (MCC) is a neuroendocrine cancer of the skin postulated to originate through Merkel cell polyomavirus (MCPyV) oncogenesis and/or by mutations in molecules implicated in the regulation of cell growth and survival. Despite the fact that MCPvV is detected more broadly within the population, only a part of the infected people also develop MCC. It is thus conceivable that together, virus and for example mutations, are necessary for disease development. However, apart from a correlation between MCPyV positivity or mutations and MCC development, less is known about the association of these factors with progressive disease.
OBJECTIVES: To analyze MCPyV positivity, load and integration in MCC as well as presence of mutations in PDGFRα and TP53 genes and correlate these with clinical features and disease progression to identify features with prognostic value for clinical progression.
METHODS: This is a study on a MCC population group of 64 patients. MCPyV positivity, load and integration in parallel to mutations in the PDGFRα and TP53 were analyzed on genomic DNA from MCC specimens. In addition, expression of PDGFRα, survivin and p53 proteins was analyzed by immunodetection in tissues specimens. All these parameters were analyzed as function of patient's disease progression status.
RESULTS: 83% of MCCs were positive for the MCPyV and among these 36% also displayed virus-T integration. Viral load ranged from 0.006 to 943 viral DNA copies/β-globin gene and was highest in patients with progressive disease. We detected more than one mutation within the PDGFRα gene and identified two new SNPs in 36% of MCC patients, whereas no mutations were found in TP53 gene. Survivin was expressed in 78% of specimens. We could not correlate either mutations in PDGFR or expression of PDGFR, p53 and surviving either to the disease progression or to the MCPyV positivity.
CONCLUSIONS: In conclusion, our data indicate that the viral positivity when associated with high viral load, correlates with poor disease outcome. Frequent mutations in the PDGFRα gene and high survivin expression were found in MCC independent of the viral positivity. These data suggest that these three factors independently contribute to Merkel cell carcinoma development and that only the viral load can be used as indicator of disease progression in virus positive patients.

Robles C, Casabonne D, Benavente Y, et al.
Seroreactivity against Merkel cell polyomavirus and other polyomaviruses in chronic lymphocytic leukaemia, the MCC-Spain study.
J Gen Virol. 2015; 96(8):2286-92 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV) has been suspected to cause chronic lymphocytic leukaemia (CLL) but previous data are inconsistent. We measured seroreactivities of nine polyomaviruses (MCPyV, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, HPyV-6, HPyV-7 and TSPyV) in 359 CLL cases and 370 controls using bead-based multiplex serology technology. We additionally tested two herpesviruses (HSV-1 and CMV). Associations between disease and viral seroreactivities were assessed using logistic regression. All human viruses showed high seroprevalences (69-99%) against structural proteins in controls but significantly lower viral seroprevalences in cases (58-94%; OR range = 0.21-0.70, P value < 0.05), except for MCPyV (OR = 0.79, 95% CI = 0.54-1.16). Lower seroreactivity levels were observed among CLL subjects, with significant differences already observed at early stages of disease, unrelated to treatment status. Seroreactivities against polyomavirus related oncoproteins were almost null. Our data suggest no association for MCPyV polyomavirus with CLL development and an unlikely association for other polyomaviruses tested.

Santos-Juanes J, Fernández-Vega I, Fuentes N, et al.
Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis.
Br J Dermatol. 2015; 173(1):42-9 [PubMed] Related Publications
Several observational studies have assessed the correlation between Merkel cell carcinoma and Merkel cell polyomavirus with variable results. The objective of this systematic review was to determine whether there is a correlation between Merkel cell carcinoma and Merkel cell polyomavirus. Studies assessing the relationship between Merkel cell carcinoma and Merkel cell polyomavirus from January 2008 to August 2014 were pooled from Medline, Embase, PubMed, Cochrane Database of Systemic Reviews and Google Scholar. From each study we collected the first author's last name, publication year, country of origin, type of study design, characteristics of participants, possible variables incorporated into the multivariable analyses and the risk ratio (RR) for Merkel cell carcinoma associated with Merkel cell polyomavirus combined with the corresponding 95% confidence interval (CI). Methodological assessment of the study was evaluated using the Newcastle-Ottawa scale. Crude RR was calculated from the data provided in each article. Meta-analyses for the global RR and for the proportion of positives in both case and control samples were performed. In addition, in order to explore the sources of heterogeneity among the studies, meta-regression and sensitivity analyses are also provided. A total of 22 studies were identified for the analysis. The pooled RR from random-effects analysis was determined to be 6.32 (95% CI, 4.02-9.93). Global proportions of positive samples were 0.79 (95% CI, 0.72-0.84) and 0.12 (95% CI, 0.08-0.19) in the case and control groups, respectively. The findings support the association between Merkel cell carcinoma and Merkel cell polyomavirus. However, a non-negligible percentage of positive results have been identified in controls. Some caution must be taken in the interpretation of these results because heterogeneity between studies was found.

Chatzinasiou F, Papadavid E, Korkolopoulou P, et al.
An unusual case of diffuse Merkel cell carcinoma successfully treated with low dose radiotherapy.
Dermatol Ther. 2015 Sep-Oct; 28(5):282-6 [PubMed] Related Publications
Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of the skin. MCC should be included in the diagnosis of a rapidly growing infiltrating mass and histology as well as laboratory investigations such as Merkel cell polyoma virus (MCPyV) detection are valuable in its diagnosis. We present an unusual case of giant MCC-positive MCPyV in a Greek woman located on the lower leg. Our patient is very unusual in terms of her extensive MCC and her rapid and complete response to radiotherapy.

Trizuljak J, Srovnal J, Plevová K, et al.
Analysis of prognostic significance of merkel cell polyomavirus in chronic lymphocytic leukemia.
Clin Lymphoma Myeloma Leuk. 2015; 15(7):439-42 [PubMed] Related Publications
BACKGROUND: Merkel cell polyomavirus (MCPyV), a ubiquitous DNA tumor virus, has been found to be associated with Merkel cell carcinoma and chronic lymphocytic leukemia (CLL). Previous studies have reported conflicting results on the frequency and potential pathogenetic role of MCPyV in CLL. The aim of this study was to evaluate MCPyV's association with CLL and its prognostic significance.
PATIENTS AND METHODS: Between 2006 and 2013, DNA samples obtained from CLL patients (n = 119) before treatment were tested for MCPyV using quantitative real-time polymerase chain reaction analysis and verified by gel electrophoresis. Only samples testing positive by both methods were considered valid.
RESULTS: We found that 13 (11%) of 119 CLL cases were positive for MCPyV. Between the groups of MCPyV-positive and -negative patients, there was no significant difference in the sex, age, cytogenetics, presence of p53 defect, or immunoglobulin heavy chain (IGHV) mutational status. In the subset of MCPyV-negative patients, advanced Rai stage (III to IV) was found more frequently, and therapy was initiated more often. There was no difference in overall response rate, median progression-free survival, and overall survival between both groups. We did not observe any new positivity after treatment in initially MCPyV-negative patients.
CONCLUSION: This study provides the first analysis of the prognostic role of MCPyV in CLL. MCPyV occurrence seems to be a relatively rare event during the course of CLL. MCPyV is also unlikely to influence the outcome of CLL patients.

Sadeghi F, Salehi-Vaziri M, Alizadeh A, et al.
Detection of Merkel cell polyomavirus large T-antigen sequences in human central nervous system tumors.
J Med Virol. 2015; 87(7):1241-7 [PubMed] Related Publications
Despite decades of epidemiological investigation, little is known about the etiology of the central nervous system (CNS) tumors, and few well-established risk factors have been recognized. This study tested the presence of Merkel cell polyomavirus (MCPyV), the only member of the Polyomaviridae family convincingly linked to human cancer, in diverse CNS malignancies. In total, 58 CNS tumor biopsies were analyzed for the MCPyV large T-antigen (LT-Ag) gene by quantitative real-time PCR. Merkel cell polyomavirus LT-Ag DNA load was determined as viral copies per cell and viral copies per microliter of purified genomic DNA from CNS tumor samples. The MCPyV LT-Ag sequence was detected in 34 (58.6%) of the 58 tested samples. Viral LT-Ag was quantified in 19.0% of schwannomas, 13.8% of meningiomas, and 5.2% of pituitary adenomas. The difference between MCPyV positivity in different types of CNS malignancies was not statistically significant (P = 0.066). The mean LT-Ag copy number in 34 positive samples was 744.5 ± 737.7 and 0.056 × 10(-3)  ± 0.091 × 10(-3) per microliter and per cell, respectively. Among MCPyV-positive CNS tumors, the mean MCPyV copy number was higher in meningiomas (993.8 ± 853.2 copy per microliter and 0.098 × 10(-3)  ± 0.108 × 10(-3) copy per cell). Multiple linear regression analysis revealed statistically significant difference in MCPyV copy number between meningioma and other CNS tumor types, when the model was adjusted for age and sex (P = 0.024). This study shows the first evidence of the detection of MCPyV LT-Ag sequence at a low copy number in human CNS tumors.

Salehi-Vaziri M, Sadeghi F, Alamsi-Hashiani A, et al.
Merkel cell polyomavirus and human papillomavirus infections in cervical disease in Iranian women.
Arch Virol. 2015; 160(5):1181-7 [PubMed] Related Publications
Human papillomavirus (HPV) infection is a necessary cause of cervical neoplasia. Concomitant infection with other infectious agents has been demonstrated to be a cofactor for HPV-related cervical carcinogenesis. The present investigation aimed to determine the prevalence of HPV and Merkel cell polyomavirus (MCPyV) infections and to evaluate the role of MCPyV as a co-factor for HPV-related cervical carcinogenesis in Iranian women. From 2011 to 2013, a total of 112 cervical samples were examined. Forty-five samples (40.2 %) were positive for HPV. MCPyV was found in 37 samples (33 %). Both HPV and MCPyV were present in 14 samples (12.5 %). MCPyV was seen in 30 % of squamous cell carcinomas, 37.5 % of adenocarcinomas, and 16.7 % of undifferentiated carcinomas. The MCPyV large T antigen (LT-Ag) DNA load was determined as the viral copy number per cell. The median MCPyV LT-Ag copy number in positive women was 0.049 × 10(-3) per cell (range 0.0006 × 10(-3)-4.558 × 10(-3) copies per cell). In comparison with other types of cervical cancer, the MCPyV LT-Ag load was higher in adenocarcinomas (0.1024 × 10(-3) copies per cell). A logistic regression model adjusted to HPV positivity and age revealed no statistically significant association between MCPyV infection and cervical cancer (OR, 1.12; 95 % CI, 0.07-16.83). More studies should be conducted to clarify the role of MCPyV in cervical carcinogenesis.

Sourvinos G, Mammas IN, Spandidos DA
Merkel cell polyomavirus infection in childhood: current advances and perspectives.
Arch Virol. 2015; 160(4):887-92 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV) is a newly discovered human small, non-enveloped, double-stranded DNA virus, which was classified into the Polyomaviridae family. MCPyV is acquired in early childhood through close contact involving respiratory tract secretions and causes a widespread, previously unrecognised, asymptomatic infection in both immunocompetent children and adults. To date, several researchers have established that MCPyV is the potential causative agent of Merkel cell carcinoma, a relatively rare but life-threatening skin cancer of neuroendocrine origin. In our review, we present current data on the presence of MCPyV DNA in children and address the possible role that the respiratory tract plays in the route of viral transmission. Future studies are required to fully elucidate the potential implications of MCPyV infection in children.

Kwun HJ, Shuda M, Camacho CJ, et al.
Restricted protein phosphatase 2A targeting by Merkel cell polyomavirus small T antigen.
J Virol. 2015; 89(8):4191-200 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
UNLABELLED: Merkel cell polyomavirus (MCV) is a newly discovered human cancer virus encoding a small T (sT) oncoprotein. We performed MCV sT FLAG-affinity purification followed by mass spectroscopy (MS) analysis, which identified several protein phosphatases (PP), including PP2A A and C subunits and PP4C, as potential cellular interacting proteins. PP2A targeting is critical for the transforming properties of nonhuman polyomaviruses, such as simian virus 40 (SV40), but is not required for MCV sT-induced rodent cell transformation. We compared similarities and differences in PP2A binding between MCV and SV40 sT. While SV40 sT coimmunopurified with subunits PP2A Aα and PP2A C, MCV sT coimmunopurified with PP2A Aα, PP2A Aβ, and PP2A C. Scanning alanine mutagenesis at 29 sites across the MCV sT protein revealed that PP2A-binding domains lie on the opposite molecular surface from a previously described large T stabilization domain (LSD) loop that binds E3 ligases, such as Fbw7. MCV sT-PP2A interactions can be functionally distinguished by mutagenesis from MCV sT LSD-dependent 4E-BP1 hyperphosphorylation and viral DNA replication enhancement. MCV sT has a restricted range for PP2A B subunit substitution, inhibiting only the assembly of B56α into the phosphatase holoenzyme. In contrast, SV40 sT inhibits the assembly of B55α, B56α and B56ε into PP2A. We conclude that MCV sT is required for Merkel cell carcinoma growth, but its in vitro transforming activity depends on LSD interactions rather than PP2A targeting.
IMPORTANCE: Merkel cell polyomavirus is a newly discovered human cancer virus that promotes cancer, in part, through expression of its small T (sT) oncoprotein. Animal polyomavirus sT oncoproteins have been found to cause experimental tumors by blocking the activities of a group of phosphatases called protein phosphatase 2A (PP2A). Our structural analysis reveals that MCV sT also displaces the B subunit of PP2A to inhibit PP2A activity. MCV sT, however, only displaces a restricted subset of PP2A B subunits, which is insufficient to cause tumor cell formation in vitro. MCV sT instead transforms tumor cells through another region called the large T stabilization domain. The PP2A targeting and transforming activities lie on opposite faces of the MCV sT molecule and can be genetically separated from each other.

Andea AA, Patel R, Ponnazhagan S, et al.
Detection of Merkel cell polyomavirus in formalin-fixed, paraffin-embedded tissue of Merkel cell carcinoma and correlation with prognosis.
Rom J Morphol Embryol. 2014; 55(3 Suppl):1057-62 [PubMed] Related Publications
Merkel cell carcinoma (MCC) is a rare, but highly aggressive primary cutaneous malignancy, showing neuroendocrine differentiation. In 2008, a novel member of the polyomavirus family, named Merkel cell polyomavirus (MCPyV) was identified in the genome of MCC tumors raising the possibility of an involvement in its pathogenesis. Due to the rarity of this tumor and current pathology practices, the most readily available tissue is archival formalin-fixed, paraffin-embedded (FFPE) material. In this study, we evaluated the presence of MCPyV in FFPE tissue and correlated its presence with tumor progression. Representative FFPE specimens from 18 tumors belonging to 14 patients with a diagnosis of MCC spanning the period from 2003 to 2008 were retrieved. Following DNA extraction, we performed PCR amplification and sequencing with four different MCPyV-specific primer pairs mapping within the T antigen and VP1 region. Overall, we detected MCPyV amplicons in 8/18 (44.4%) analyzed tumors from 7/14 (50%) cases. Two-year survival rate and median survival for the MCPyV-positive MCCs were 48% and 22.5 months, respectively and for the negative ones 69% and 51.3 months, respectively; however, the difference did not reach statistical significance (p=0.8). There was no significant correlation between the presence of the virus and the stage at presentation; however, tumors in the head and neck area had a lower frequency of viral positivity compared to those arising in the extremities suggesting a MCPyV-independent oncogenetic pathway perhaps, dependent on UV exposure, in a subset of these cases.

Veija T, Sahi H, Koljonen V, et al.
miRNA-34a underexpressed in Merkel cell polyomavirus-negative Merkel cell carcinoma.
Virchows Arch. 2015; 466(3):289-95 [PubMed] Related Publications
Merkel cell polyomavirus (MCV) is frequently detectable in Merkel cell carcinoma (MCC) tumors, but the significance of MCV infection is not yet totally understood. Thus far, no key regulatory miRNA has been identified for MCC tumorigenesis. However, distinct miRNA expression profiles have been suggested for MCV-positive and MCV-negative tumors. We used microarray hybridization to identify miRNA expression differences in MCC tumor samples according to MCV status and further validated these results by quantitative reverse transcription polymerase chain reaction (qRT-PCR). When compared with MCV-negative tumors, we detected overexpression of miR-34a, miR-30a, miR-142-3p, and miR-1539 in those MCV positives. In addition, slight underexpression was detectable in MCV-positive tumors of miR-181d. We confirmed the distinct expression of miRNAs in MCV-positive and MCV-negative tumors and confirmed statistically significant underexpression of miR-34a in MCV-negative tumors by both array analysis and qRT-PCR. Neither tumor location nor development of metastases affected miRNA expression.

Iwasaki T, Matsushita M, Nonaka D, et al.
Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas.
Hum Pathol. 2015; 46(2):210-6 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV) integrates monoclonally into the genomes of approximately 80% of Merkel cell carcinomas (MCCs), affecting their clinicopathological features. The molecular mechanisms underlying MCC development after MCPyV infection remain unclear. We investigated the association of MCPyV infection with activation of the Akt/mammalian target of rapamycin (mTOR)/4E-binding protein 1 (4E-BP1) signaling pathway in MCCs to elucidate the role of these signal transductions and to identify molecular targets for treatment. We analyzed the molecular and pathological characteristics of 41 MCPyV-positive and 27 MCPyV-negative MCCs. Expression of mTOR, TSC1, and TSC2 messenger RNA was significantly higher in MCPyV-negative MCCs, and Akt (T308) phosphorylation also was significantly higher (92% vs 66%; P = .019), whereas 4E-BP1 (S65 and T70) phosphorylation was common in both MCC types (92%-100%). The expression rates of most other tested signals were high (60%-100%) and not significantly correlated with MCPyV large T antigen expression. PIK3CA mutations were observed more frequently in MCPyV-positive MCCs (6/36 [17%] vs 2/20 [10%]). These results suggest that protein expression (activation) of most Akt/mTOR/4E-BP1 pathway signals was not significantly different in MCPyV-positive and MCPyV-negative MCCs, although these 2 types may differ in tumorigenesis, and MCPyV-negative MCCs showed significantly more frequent p-Akt (T308) activation. Therefore, certain Akt/mTOR/4E-BP1 pathway signals could be novel therapeutic targets for MCC regardless of MCPyV infection status.

Fisher CA, Harms PW, McHugh JB, et al.
Small cell carcinoma in the parotid harboring Merkel cell polyomavirus.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2014; 118(6):703-12 [PubMed] Related Publications
OBJECTIVE: This study aimed to document three new cases of primary small cell carcinoma (SmCC) of the parotid and examine immunohistochemical and quantitative real-time polymerase chain reaction (qPCR) data of the recently developed Merkel cell polyomavirus (MCPyV) within these tumors.
STUDY DESIGN: Immunohistochemistry for neuroendocrine markers (chromogranin A, CD56, CD57, neuron-specific enolase [NSE], thyroid transcription factor 1 [TTF-1]), epithelial markers (CK20, CK7, CAM 5.2), and MCPyV large T antigen (LTAg) were examined. qPCR and Sanger sequencing were performed to confirm the presence of the MCPyV LTAg gene.
RESULTS: Two males and one female, average age 76 years, presented with left parotid masses. Clinical examinations, histories, and imaging studies were negative for cutaneous Merkel cell carcinoma (MCC), pulmonary and extrapulmonary SmCC, or any other malignancy. Immunohistochemical analysis demonstrated positive immunoreactivity for CK20 in a perinuclear dotlike pattern (3/3), CAM 5.2 (3/3), (2/3), NSE (3/3), CD56 (2/3), and CD57 (3/3). Two cases stained positive for MCPyV, showing moderate to strong, diffuse positivity, confirmed with qPCR. PCR-Sanger sequencing of LTAg exon 2 showed greater than 97% similarity to the MCPyV reference genome in both cases.
CONCLUSION: Our findings expand the number of reported cases classified as primary parotid SmCC that harbors MCPyV and underscore the similarity between cutaneous MCC and parotid SmCC. Further investigation is needed to determine whether immune-based therapeutic strategies targeting MCPyV in MCC are also effective in the setting of parotid SmCC harboring MCPyV.

Samimi M, Touzé A
Merkel cell carcinoma: The first human cancer shown to be associated with a polyomavirus.
Presse Med. 2014; 43(12 Pt 2):e405-11 [PubMed] Related Publications
Merkel cell carcinoma (MCC) is a rare, malignant primary neuroendocrine cancer of the skin, usually affecting elderly, white people in sun-exposed areas. This is a highly aggressive tumor with strong propensity to metastasize. Surgery and radiation therapy remain the mainstay of treatment, with no curative treatment in case of disseminated metastases. Until 2008, MCC was thought to be caused by the malignant transformation of resident Merkel cells, but no investigation of a predominant molecular pathway that could be involved in MCC pathogenesis was successful. A real revolution in MCC understanding and management occurred in 2008, when a new human polyomavirus (MCPyV) was found to be the main etiological agent of this skin cancer. Following the discovery of MCPyV, the association of MCPyV with MCC has been confirmed worldwide, with detection of MCPyV in about 80% of MCCs. At the same time it had been shown that MCPyV infection is almost ubiquitous in healthy subjects, and MCPyV is thought to be persistent resident of the skin microbiome although the route of transmission, the host cell, the viral cycle and/or latency remain unknown. Most studies suggest that there may be two subtypes of MCC: MCPyV-positive (80%) and MCPyV-negative (20%) MCCs, and various studies have reported a better prognosis associated with MCPyV infection. The discovery of MCPyV in MCC patients opens up new therapeutic insights. The necessity and persistence of expression of MCPyV oncoproteins during MCC development make these proteins promising therapeutic targets.

Miner AG, Patel RM, Wilson DA, et al.
Cytokeratin 20-negative Merkel cell carcinoma is infrequently associated with the Merkel cell polyomavirus.
Mod Pathol. 2015; 28(4):498-504 [PubMed] Related Publications
Merkel cell carcinoma is a rare, highly aggressive cutaneous neuroendocrine carcinoma most commonly seen in sun-damaged skin. Histologically, the tumor consists of primitive round cells with fine chromatin and numerous mitoses. Immunohistochemical stains demonstrate expression of neuroendocrine markers. In addition, cytokeratin 20 (CK20) is expressed in ∼95% of cases. In 2008, Merkel cell carcinoma was shown to be associated with a virus now known as Merkel cell polyomavirus in ∼80% of cases. Prognostic and mechanistic differences between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative Merkel cell carcinoma may exist. There has been the suggestion that CK20-negative Merkel cell carcinomas less frequently harbor Merkel cell polyomavirus, but a systematic investigation for Merkel cell polyomavirus incidence in CK20-negative Merkel cell carcinoma has not been done. To test the hypothesis that Merkel cell polyomavirus is less frequently associated with CK20-negative Merkel cell carcinoma, we investigated 13 CK20-negative Merkel cell carcinomas from the files of the Cleveland Clinic and the University of Michigan for the virus. The presence or absence of Merkel cell polyomavirus was determined by quantitative PCR performed for Large T and small T antigens, with sequencing of PCR products to confirm the presence of Merkel cell polyomavirus. Ten of these (77%) were negative for Merkel cell polyomavirus and three (23%) were positive for Merkel cell polyomavirus. Merkel cell polyomavirus is less common in CK20-negative Merkel cell carcinoma. Larger series and clinical follow-up may help to determine whether CK20-negative Merkel cell carcinoma is mechanistically and prognostically unique.

Freze Baez C, Cirauqui Diaz N, Baeta Cavalcanti SM, Brandão Varella R
Genetic and structural analysis of Merkel cell polyomavirus large T antigen from diverse biological samples.
Intervirology. 2014; 57(6):331-6 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV) large T antigen (LT-ag) is frequently found truncated in Merkel cell carcinomas (MCC) and it is considered a major tumor-specific signature. Nonetheless, the biological role of LT-ag nontruncated mutations is largely unknown. In this study, MCPyV LT-ag second exon from 11 non-MCC oral samples and NCBI sequences derived from different anatomical sites were studied from the genetic and structural standpoint. As expected, the LT-ag mutation profile was influenced by the geographical origin of the sample, although nonsynonymous mutations were more frequent in lesional tissues. Our in silico study suggests that the mutations found would not significantly affect protein functions, regardless of sample category. This work presents a thorough investigation of the structural and functional properties of LT-ag nontruncated mutations in MCPyV. Our results sustain the geographical influence of the MCPyV genetic profile, but do not discard genetic tissue specificities. Further investigation involving other genetic segments in healthy and lesional tissues are necessary to improve our knowledge on MCPyV pathogenesis.

Karimi S, Yousefi F, Seifi S, et al.
No evidence for a role of Merkel cell polyomavirus in small cell lung cancer among Iranian subjects.
Pathol Res Pract. 2014; 210(12):836-9 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV), as a new member of polyomaviruses, has recently been discovered as a possible etiologic factor for human cancer. It was first detected in Merkel cell carcinoma (MCC). Small cell lung cancer (SCLC) is a malignant lung tumor which shares histopathological and genetic features with MCC, as both are of neuroendocrine origin. In this study, we investigated the presence of MCPyV DNA in SCLC specimens by real-time PCR. Our null hypothesis was that MCPyV is an etiologic factor in SCLC, as previously seen in MCC. Formalin-fixed and paraffin-embedded (FFPE) specimens were obtained from 50 patients, who underwent bronchoscopic biopsy and were diagnosed with SCLC between March 2010 and March 2012. Similarly, we obtained bronchoscopic biopsy specimens from 29 patients, who were diagnosed with non-small cell lung cancer (NSCLC). All samples were obtained at a single center (Masih Daneshvari Hospital, Tehran, Iran). Real-time PCR was done to detect the presence of MCPyV DNA. After excluding one specimen from the SCLC group due to loss of tumor tissue, we did not detect MCPyV DNA in samples from patients with either SCLC (the mean age 58.9 years, male/female ratio: 7.3/1) or NSCLC. Our results suggest that MCPyV does not play a role in the pathogenesis of SCLC, which is in accord with the results from other prior investigations.

Houben R, Angermeyer S, Haferkamp S, et al.
Characterization of functional domains in the Merkel cell polyoma virus Large T antigen.
Int J Cancer. 2015; 136(5):E290-300 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV)--positive Merkel cell carcinoma (MCC) tumor cell growth is dependent on the expression of a viral Large T antigen (LT) with an intact retinoblastoma protein (RB)-binding site. This RB-binding domain in MCPyV-LT is--in contrast to other polyomavirus LTs (e.g., SV40)--embedded between two large MCPyV unique regions (MUR1 and MUR2). To identify elements of the MCPyV-LT necessary for tumor cell growth, we analyzed the rescue activity of LT variants following knockdown of the endogenous LT in MCC cells. These experiments demonstrate that nuclear localization is essential for LT function, but that a motif previously described to be a nuclear localization sequence is neither required for nuclear accumulation of truncated MCPyV-LT nor for promotion of MCC cell proliferation. Furthermore, large parts of the MURs distal to the RB binding domain as well as ALTO--a second protein encoded by an alternative reading frame in the MCPyV-LT mRNA--are completely dispensable for MCPyV-driven tumor cell proliferation. Notably, even MCPyV-LTs in which the entire MURs have been removed are still able to promote MCC cellular growth although rescue activity is reduced which may be due to MUR1 being required for stable LT expression in MCC cells. Finally, we provide evidence implying that--while binding to Vam6p is not essential--HSC-70 interaction is significantly involved in mediating MCPyV-LT function in MCC cells including growth promotion and induction of E2F target genes.

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