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Merkel cell polyomavirus (MCPyV) is a significant contributor to the development of Merkel cell carcinoma (MCC), an aggressive skin cancer with high recurrence and a low survival rate. In fact, it is the deadliest skin cancer. The precise routes of transmission for MCPyV‐positive MCC remain unclear, but several factors may trigger its development. Conventional treatments for MCC are not highly effective, especially in patients with metastasis, with a clear need for new treatment options. Gene‐targeted therapies hold great promise for the treatment of MCC, including the use of siRNA and CRISPR/Cas (C/Cas) but critically none have yet been translated into clinical trials. Validating this approach is the fact that several siRNA products are already FDA licenced, while C/Cas has entered clinical trial, albeit for conditions other than MCC. There are many challenges that must be overcome to move from preclinical research to the clinic. In this review, we provide a comprehensive summary of the current understanding of MCC, with a particular focus on MCPyV‐positive MCC, and the status of gene‐targeted therapies. Additionally, we discuss the major obstacles that impede MCC research and explore future prospects. [ABSTRACT FROM AUTHOR]

About 15% of all human cancers have a viral etiology. Although progress has been made, understanding the viral oncogenesis and associated molecular mechanisms remain complex. The discovery of cellular miRNAs has led to major breakthroughs. Interestingly, viruses have also been discovered to encode their own miRNAs. These viral, small, non-coding miRNAs are also known as viral-miRNAs (v-miRNAs). Although the function of v-miRNAs largely remains to be elucidated, their role in tumorigenesis cannot be ignored. V-miRNAs have also been shown to exploit the cellular machinery to benefit viral replication and survival. Although the discovery of Hepatitis C virus (HCV), and its viral miRNAs, is a work in progress, the existence of HPV-, EBV-, HBV-, MCPyV- and KSHV-encoded miRNA has been documented. V-miRNAs have been shown to target host factors to advance tumorigenesis, evade and suppress the immune system, and deregulate both the cell cycle and the apoptotic machinery. Although the exact mechanisms of v-miRNAs-induced tumorigenesis are still unclear, v-miRNAs are active role-players in tumorigenesis, viral latency and cell transformation. Furthermore, v-miRNAs can function as posttranscriptional gene regulators of both viral and host genes. Thus, it has been proposed that v-miRNAs may serve as diagnostic biomarkers and therapeutic targets for cancers with a viral etiology. Although significant challenges exist in their clinical application, emerging reports demonstrate their potent role in precision medicine. This review will focus on the roles of HPV-, HCV-, EBV-, HBV-, MCPyV-, and KSHV-produced v-miRNAs in tumorigenesis, as effectors in immune evasion, as diagnostic biomarkers and as novel anti-cancer therapeutic targets. Finally, it will discuss the challenges and opportunities associated with v-miRNAs theranostics in precision oncology. [ABSTRACT FROM AUTHOR]

About 15% of all human cancers have a viral etiology. Although progress has been made, understanding the viral oncogenesis and associated molecular mechanisms remain complex. The discovery of cellular miRNAs has led to major breakthroughs. Interestingly, viruses have also been discovered to encode their own miRNAs. These viral, small, non-coding miRNAs are also known as viral-miRNAs (v-miRNAs). Although the function of v-miRNAs largely remains to be elucidated, their role in tumorigenesis cannot be ignored. V-miRNAs have also been shown to exploit the cellular machinery to benefit viral replication and survival. Although the discovery of Hepatitis C virus (HCV), and its viral miRNAs, is a work in progress, the existence of HPV-, EBV-, HBV-, MCPyV- and KSHV-encoded miRNA has been documented. V-miRNAs have been shown to target host factors to advance tumorigenesis, evade and suppress the immune system, and deregulate both the cell cycle and the apoptotic machinery. Although the exact mechanisms of v-miRNAs-induced tumorigenesis are still unclear, v-miRNAs are active role-players in tumorigenesis, viral latency and cell transformation. Furthermore, v-miRNAs can function as posttranscriptional gene regulators of both viral and host genes. Thus, it has been proposed that v-miRNAs may serve as diagnostic biomarkers and therapeutic targets for cancers with a viral etiology. Although significant challenges exist in their clinical application, emerging reports demonstrate their potent role in precision medicine. This review will focus on the roles of HPV-, HCV-, EBV-, HBV-, MCPyV-, and KSHV-produced v-miRNAs in tumorigenesis, as effectors in immune evasion, as diagnostic biomarkers and as novel anti-cancer therapeutic targets. Finally, it will discuss the challenges and opportunities associated with v-miRNAs theranostics in precision oncology.

About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer caused either by Merkel cell polyomavirus (MCV) T antigen expression, post-integration (~80% cases), or by UV-mediated DNA damage. Interestingly, overall survival of MCV-positive Merkel cell carcinoma patients is better, making this differential information of significant diagnostic and prognostic value. Also, MCV provides a direct target for therapy in MCC patients. Currently, the methods used for diagnosis of MCV in tumors are often discordant and unreliable. Here we used a guided molecular scissors based–DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR) technique to develop an in vitro molecular diagnostic tool for MCV-positive MCC. DETECTR couples recombinase polymerase based amplification of target MCV DNA with Cas12a mediated detection. CRISPR diagnostics couple specific detection followed by cutting of the pathogenic DNA by the Cas enzyme–gRNA complex, with non-specific cutting of ssDNA that provides a measurable visual cue. To detect MCV DNA in MCC, we designed Cas12a gRNAs targeting the MCV DNA and tested their targeting efficiency, and sensitivity using a fluorophore quencher labeled reporter assay. We show that MCV DETECTR system can detect MCV integrated in Merkel tumor rapidly, specifically and with femto-molar sensitivity. Our study is a preliminary, proof-of-principle analysis showing the use of CRISPR for MCV diagnosis. Further validation in human tumor samples is needed for its clinical use in the near future. This new system is promising and we hope it can be coupled with immunohistochemical studies to diagnose the viral status of MCC in clinics soon.

Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin. This neoplasia features aggressive behavior, resulting in a 5-year overall survival rate of 40%. In 2008, Feng et al. identified Merkel cell polyomavirus (MCPyV) integration into the host genome as the main event leading to MCC oncogenesis. However, despite identification of this crucial viral oncogenic trigger, the nature of the cell in which MCC oncogenesis occurs is actually unknown. In fact, several hypotheses have been proposed. Despite the large similarity in phenotype features between MCC tumor cells and physiological Merkel cells (MCs), a specialized subpopulation of the epidermis acting as mechanoreceptor of the skin, several points argue against the hypothesis that MCC derives directly from MCs. Alternatively, MCPyV integration could occur in another cell type and induce acquisition of an MC-like phenotype. Accordingly, an epithelial as well as a fibroblastic or B-cell origin of MCC has been proposed mainly based on phenotype similarities shared by MCC and these potential ancestries. The aim of this present review is to provide a comprehensive review of the current knowledge of the histogenesis of MCC.

Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin. This neoplasia features aggressive behavior, resulting in a 5-year overall survival rate of 40%. In 2008, Feng et al. identified Merkel cell polyomavirus (MCPyV) integration into the host genome as the main event leading to MCC oncogenesis. However, despite identification of this crucial viral oncogenic trigger, the nature of the cell in which MCC oncogenesis occurs is actually unknown. In fact, several hypotheses have been proposed. Despite the large similarity in phenotype features between MCC tumor cells and physiological Merkel cells (MCs), a specialized subpopulation of the epidermis acting as mechanoreceptor of the skin, several points argue against the hypothesis that MCC derives directly from MCs. Alternatively, MCPyV integration could occur in another cell type and induce acquisition of an MC-like phenotype. Accordingly, an epithelial as well as a fibroblastic or B-cell origin of MCC has been proposed mainly based on phenotype similarities shared by MCC and these potential ancestries. The aim of this present review is to provide a comprehensive review of the current knowledge of the histogenesis of MCC. [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases per year in the United States, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV oncoprotein (T-antigens) have been correlated with MCC tumor burden. The present study assesses the clinical utility of MCPyV-oncoprotein antibody titers for MCC prognostication and surveillance.Methods: MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly diagnosed MCC were followed prospectively (median follow-up, 1.9 years). Among the seropositive patients, antibody titer and disease status were serially tracked.Results: Antibodies to MCPyV oncoproteins were rare among healthy individuals (1%) but were present in most patients with MCC (114 of 219 patients [52%]; P < .01). Seropositivity at diagnosis independently predicted decreased recurrence risk (hazard ratio, 0.58; P = .04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. After initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 time points), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence, whereas a decreasing titer had a negative predictive value of 97%.Conclusions: Determination of oncoprotein antibody titer assists in the clinical management of patients with newly diagnosed MCC by stratifying them into a higher risk seronegative cohort, in which radiologic imaging may play a more prominent role, and into a lower risk seropositive cohort, in which disease status can be tracked in part by oncoprotein antibody titer. Cancer 2017;123:1464-1474. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Viral infections of the anal/rectal tract of men who have sex with men (MSM) have been poorly studied. Methods: In total, 158 swab samples (81 anal/rectal, 65 throat/oral and 12 urethral) were collected from 126 MSM. DNA was isolated and subjected to real-time PCR assays for the detection of the sexually transmitted (ST) pathogens Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasmas ssp, human papillomavirus (HPV) and six human polyomaviruses (HPyVs; JCPyV, BKPyV, Merkel cell PyV⁻MCPyV-, HPyV-6, HPyV-7 and HPyV-9). Results: C. trachomatis (31/126, 24.6%) and M. genitalium (30/126, 23.8%) were the most frequently detected ST pathogens. Thirty-one/126 (24.6%) patients were positive for at least one HPyV. The significantly (p < 0.05) prevalent HPyV in the anal tract was MCPyV, which was amplified in 27/81 (33.3%) samples, followed by HPyV-6, which was amplified in 6/81 (7.4%) swabs. Coinfections with MCPyV and C. trachomatis or Mycoplasmas were found in 4/21 (19.0%) and 5/21 (23.8%) anal/rectal swabs, respectively. Three/4 MCPyV-C. trachomatis coinfected patients were symptomatic. Conclusions: Based on the high prevalence of MCPyV in the anal/rectal swabs from MSM patients and on the well-known oncogenic properties of MCPyV, sexual transmission and possible involvement of HPyVs in the pathogenesis of diseases of the anal canal should be further studied.

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. © 2015 Wiley Periodicals, Inc. Head Neck, 2015 © 2015 Wiley Periodicals, Inc. Head Neck 38: 647-652, 2016 [ABSTRACT FROM AUTHOR]

Abstract: Virus-like particles (VLPs), aggregates of capsid proteins devoid of viral genetic material, show great promise in the fields of vaccine development and gene therapy. These particles spontaneously self-assemble after heterologous expression of viral structural proteins. This review will focus on the use of virus-like particles derived from polyomavirus capsid proteins. Since their first recombinant production 27years ago these particles have been investigated for a myriad of biomedical applications. These virus-like particles are safe, easy to produce, can be loaded with a broad range of diverse cargos and can be tailored for specific delivery or epitope presentation. We will highlight the structural characteristics of polyomavirus-derived VLPs and give an overview of their applications in diagnostics, vaccine development and gene delivery. [Copyright &y& Elsevier]

Merkel cell polyomavirus infects up to 80% of patients with Merkel cell carcinoma. Combined Merkel cell carcinoma and cutaneous tumors occur occasionally. Previous reports have suggested that Merkel cell polyomavirus is absent from combined Merkel cell carcinoma and squamous cell carcinomas. This is the first report that Merkel cell polyomavirus infected in both lesions of a combined Merkel cell carcinoma and basal cell carcinoma. A 92-year-old Japanese man presented with a right thigh small subcutaneous mass. Histologic examination revealed a combined tumor with Merkel cell carcinoma and basal cell carcinoma with ductal differentiation. Both tumors and intermingled Merkel cells in basal cell carcinoma expressed Merkel cell polyomavirus large T antigen, and 17 and 240 copies of Merkel cell polyomavirus/cell were detected in the microdissected Merkel cell carcinoma and basal cell carcinoma specimens, respectively. Mutation analysis of Merkel cell polyomavirus large T antigen revealed a novel truncating mutation in Merkel cell carcinoma and a similar but different mutation in the basal cell carcinoma. These results suggest that each was infected by a different Merkel cell polyomavirus subclone derived from a single Merkel cell polyomavirus. [ABSTRACT FROM AUTHOR]

In 67-100% of cutaneous Merkel cell carcinomas (MCC) the Merkel cell polyomavirus (MCPyV) integrates into the host genome. Mutations and deletions truncating the C-terminal helicase domain of the T-antigen (TAg) protein have been detected in these MCCs, but not in healthy skin specimens. C-terminal deletions of the TAg nucleic acid sequences are characteristic for about 38% of these cases. While the association of MCPyV with MCC has been proven, it is unknown whether MCPyV may play a similar role in other tumor entities. We describe in detail the development and validation of a novel Merkel cell polyomavirus TAg C-terminus deletion assay (MCPyV ΔC-TAg). The triplex real-time PCR quantifies the N- and C-terminal part of the MCPyV TAg gene and the cellular β-globin gene. By comparing the copy numbers of the N- and C-terminal part, deletions of the MCPyV TAg C-terminus are rapidly identified. MCPyV ΔC-TAg was used to assess the physical state of MCPyV TAg in a large series of 55 MCCs, 15 cutaneous lymphomas and 47 forehead smears of healthy individuals. Neither DNA positivity nor viral load was able to discriminate MCCs from the other different types of samples. However, deleted TAg C-terminus sequences were detected only in MCPyV positive MCCs (39%). Consequently, detection of deleted C-terminal TAg sequences appears to be a highly specific surrogate marker for virally induced malignancy and should be used to support novel assumed MCPyV-tumor associations. The study further supports the notion that MCPyV does not play a role in cutaneous lymphoma pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: The study of cancer is incomplete without taking into consideration of tumorigenic viruses. Initially, searches for human cancer viruses were fruitless despite an expansion of our knowledge in the same period concerning acute-transforming retroviruses in animals. However, over the last 40years, we have witnessed rapid progress in the tumor virology field. Currently, acknowledged human cancer viruses include Epstein–Barr virus, hepatitis B virus, hepatitis C virus, high-risk human papilloma viruses, human T-cell lymphotropic virus type 1 and Kaposi’s sarcoma-associated herpesvirus. Extensive epidemiological and mechanistic studies have led to the development of novel preventive and therapeutic approaches for managing some of these infections and associated cancers. In addition, recent advances in molecular technologies have enabled the discovery of a new potential human tumor virus, Merkel cell polyomavirus, but its association with cancer remains to be validated. It is anticipated that in the next few decades many additional human cancer viruses will be discovered and the mechanisms underlying viral oncogenesis delineated. Thus, it can be expected that better tools for preventing and treating virus-associated cancer will be available in the near future. [Copyright &y& Elsevier]

Summary: Recently, it has been shown that approximately 80% of Merkel cell carcinomas harbor a novel polyomavirus named Merkel cell polyomavirus, thought to be a carcinogenic agent. However, it is not fully elucidated whether Merkel cell carcinomas differ with regard to the presence or absence of Merkel cell polyomavirus. To address this, we investigated morphologic differences between Merkel cell polyomavirus–positive and –negative Merkel cell carcinomas by morphometry. Using polymerase chain reaction and real-time quantitative polymerase chain reaction, Merkel cell polyomavirus was detected in 20 (77%) of 26 Merkel cell carcinoma cases, including 4 Merkel cell carcinomas combined with squamous cell carcinomas. Interestingly, Merkel cell polyomavirus was detected only in ordinary (pure) Merkel cell carcinomas; none of the 4 combined Merkel cell carcinomas + squamous cell carcinomas was positive for Merkel cell polyomavirus (P = .001). Morphometric analyses revealed that Merkel cell polyomavirus–negative Merkel cell carcinomas had more irregular nuclei (P < .001) and more abundant cytoplasm (P = .001) than Merkel cell polyomavirus–positive Merkel cell carcinomas, which had uniform round nuclei and scant cytoplasm. Reliability of the morphometry was confirmed using intraobserver and interobserver reliability tests. These results demonstrated statistically significant differences in tumor cell morphology between Merkel cell polyomavirus–positive and –negative Merkel cell carcinomas and reconfirmed the absence of Merkel cell polyomavirus in combined tumors. Furthermore, the results strongly suggest fundamental biological differences between Merkel cell polyomavirus–positive and –negative Merkel cell carcinomas, supporting that Merkel cell polyomavirus plays an important role in the pathogenesis of Merkel cell polyomavirus–positive Merkel cell carcinoma. [Copyright &y& Elsevier]

Abstract: Background: Merkel cell polyomavirus (MCPyV) was first identified in Merkel cell carcinoma (MCC) as a new tumor virus. Studies have also reported differing frequencies of MCPyV detection in other skin cancers in western countries. Objectives: Little is known about geographical differences of MCPyV prevalence in non-MCC tumors. We examined the existence of MCPyV in non-MCC skin cancers including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in Japanese patients. Study design: Paraffin-embedded tissues of cutaneous SCC (n =30) and BCC (n =10) from Japanese patients were tested for the presence of MCPyV by polymerase chain reaction (PCR) with primer sets directed against the genes encoding large-T antigen 3 (LT3) and viral protein 1 (VP1). This was followed by DNA fragment sequencing and immunohistochemistry. Results: PCR analysis targeting the LT3 gene showed that the viral sequences were found in 4 of 30 (13%) SCC cases. Nested PCR detected the VP1 region in four cases. Sequencing analysis of these PCR-amplified fragments showed a close homology to the previously published MCPyV sequences. Immunohistochemistry with the monoclonal antibody to MCPyV LT-antigen showed positive staining in 2 of 4 LT3 PCR-positive cases. On the other hand, our BCC samples were all negative for MCPyV. Conclusion: This study suggested that Japanese cutaneous SCC is infrequently associated with MCPyV. Further worldwide epidemiological surveys are warranted to determine the possible association of MCPyV with pathogenesis of non-MCC skin cancers. [ABSTRACT FROM AUTHOR]

Abstract: Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin. MCCs and some other skin cancers, such as basal cell carcinomas, frequently harbour Merkel cell polyomavirus DNA. The purpose of the study was to investigate the frequency of second cancers following the diagnosis of MCC. We studied the incidence of second primary cancers after the diagnosis of MCC from the files of the Finnish Cancer Registry in 1979–2006. Among the 172 MCC patients identified a total of 34 second primary cancers were detected in 30 individuals after the diagnosis of MCC. Female MCC patients were diagnosed with 25 subsequent cancers (SIR, 2.35; 95% CI, 1.52–3.47; p <0.001) and male patients with 9 cancers (SIR, 2.32, 95% CI, 1.06–4.40; p <0.05). The MCC patients had an increased risk for a subsequent cancer (any site) compared to age-, gender- and calendar period-matched general population (standardized incidence ratio [SIR] 2.34; 95% confidence interval [CI], 1.62–3.27). The risks for basal cell carcinoma of the skin (O=11), SIR, 3.48; 95% CI, 1.74–6.22 and chronic lymphocytic leukemia (O=2), SIR, 17.9; 95% CI, 2.16–64.6 were significantly elevated. The SIRs for an overall second primary cancer risk did not change markedly with time since the diagnosis of MCC. We conclude that patients diagnosed with MCC have an increased risk for a second cancer. This risk may in part result from shared etiological factors between MCC and other tumour types, such as immunosuppression or possibly Merkel cell polyomavirus infection. [Copyright &y& Elsevier]

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer associated with the Merkel cell polyomavirus (MCPyV). The MCPyV genome, which is clonally integrated in the majority of MCCs, encodes the regulatory small T (sT) antigen. Previously, reports have established MCPyV sT antigen as a potent oncogene capable of inducing cell transformation. In the current study, we demonstrate a distinct role for c-Jun hyperactivation in MCPyV sT antigen pathogenesis. As MCPyV sT antigen's association with aggressive cancer growth has been previously established, this finding may represent a potential therapeutic target for the treatment of MCCs. [ABSTRACT FROM AUTHOR]

Merkel cell Polyomavirus is a non-enveloped, dsDNA virus belonging to Polyomaviridae family linked to an uncommon aggressive skin malignancy. The poor prognosis and limited understanding of disease pathogenesis warrants innovative treatment. In this current study we aim to predict T and B cell immunogenic epitopes from the VP1 protein of all merkel cell polyomavirus strain which will aid in effective epitope-based vaccine design using immuoinformatics approaches. We retrieved 423 full-length VP1 protein sequences of merkel cell polyomaviruse species from the NCBI database. These sequences were analyzed to determine the conserved region and were used to predict the epitopes using the immune epitope data base immunoinformatics algorithms. A total of nine promiscus epitopes were predicted. For B cell, three epitopes were selected as peptide vaccine (QEKTVY, KTVYPK, and QEKTVYP). For T cell the predicted Class-I peptides (SLFSNLMPK, LQMWEAISV and LLVKGGVEV) were found to cover the maximum number of MHC I alleles. The highest scoring Class II MHC binding peptides were (IELYLNPRM, ISSLINVHY and INSLFSNLM). Further in vivo experiments will need to be undertaken to confirm the potential of these predicted epitopes in a future efficacious novel vaccine development. [ABSTRACT FROM AUTHOR]

Merkel cell polyomavirus (MCPyV) is a small DNA virus with oncogenic potential. MCPyV is the causative agent of Merkel Cell Carcinoma (MCC), a rare but aggressive tumor of the skin. The role of epigenetic mechanisms, such as histone posttranslational modifications (HPTMs), DNA methylation, and microRNA (miRNA) regulation on MCPyV-driven MCC has recently been highlighted. In this review, we aim to describe and discuss the latest insights into HPTMs, DNA methylation, and miRNA regulation, as well as their regulative factors in the context of MCPyV-driven MCC, to provide an overview of current findings on how MCPyV is involved in the dysregulation of these epigenetic processes. The current state of the art is also described as far as potentially using epigenetic dysregulations and related factors as diagnostic and prognostic tools is concerned, in addition to targets for MCPyV-driven MCC therapy. Growing evidence suggests that the dysregulation of HPTMs, DNA methylation, and miRNA pathways plays a role in MCPyV-driven MCC etiopathogenesis, which, therefore, may potentially be clinically significant for this deadly tumor. A deeper understanding of these mechanisms and related factors may improve diagnosis, prognosis, and therapy for MCPyV-driven MCC. [ABSTRACT FROM AUTHOR]

Abstract: Merkel cell carcinoma (MCC) is an uncommon neuroendocrine tumour of the skin; rare cases have been reported within the lymph nodes without a primary site. The detection of Merkel cell polyomavirus (MCPyV) DNA, integrated within the genome of MCC, suggests its role for the onset of this tumour. We report a case of MCC in an inguinal lymph node of a patient with Von Willebrand disease (VWD), who underwent multiple blood transfusions following haemorrhoidectomy. The diagnosis was performed on the bases of morphology and immunohistochemistry; genomic sequences of LT and VP1 regions of MCPyV were amplified from MCC using a quantitative polymerase chain reaction (qPCR) assay. High levels of MCPyV antibodies were detected in the patient's serum by ELISA method. We discuss the role of MCPyV in the development of this tumour, the use of viral DNA detection for confirming the diagnosis of MCC in unusual sites and the possibility of MCPyV transmission from blood donors. [Copyright &y& Elsevier]

Human papillomavirus (HPV) is recognized as the most important risk factor in oral cavity cancer and pre-malignant lesions; however, the etiological association of concomitant infection with other oncogenic viruses as a co-factor has not been definitively proven. The present study aimed to determine the prevalence of co-infection with HPV, Epstein-Barr virus (EBV) and Merkel Cell PolyomaVirus (MCPyV) in oral cavity lesions in Iranian patients. One hundred and fourteen oral cavity samples, including 33 oral squamous cell carcinoma, 28 oral lichen planus, 16 oral epithelial dysplasia and 37 oral irritation fibromas were analyzed for the HPV, EBV and MCPyV infection by quantitative real-time PCR. According to histological features 32.5% and 28.9% of cases were oral irritation fibroma and oral squamous cell carcinoma, respectively. Infection with at least two viruses was detected in 21.1% of patients. In this group, co-infection with HPV/EBV was identified in 37.5% of cases, HPV/MCPyV in 29.2%, EBV/MCPyV in 12.5%, and HPV/EBV/MCPyV in 20.8%. There was no statistically significant difference between multiple infections and anatomical locations of cancer. The prevalence of triple viral infection (HPV/EBV/MCPyV) in well differentiated tumors was higher than EBV or MCPyV single infection. This study revealed that co-infection of HPV, EBV and MCPyV can be detected in both malignant and non-malignant oral cavity tissues, and co-infection with all three viruses in well differentiated tumors can be shown as a synergistic hypothesis of the pathogenic role of these viruses in oral malignant transformation., Competing Interests: The authors declare no conflict of interest.

Objective: Infection with human tumor viruses is one of the hypothesized causes of cancer. The current investigation aimed to explore the presence and quantitative analysis of a new human tumor virus, Merkel cell polyomavirus (MCPyV) in tissue samples of 114 patients with oral cavity lesions including oral squamous cell carcinoma (OSCC), oral lichen planus (OLP), Dysplasia and oral irritation fibroma (OIF) in Northern Iran., Methods: From 114 formalin fixed paraffin embedded samples; 35 with SCC, 29 with OLP, 14 with dysplasia and 36 with OIF were cut, deparaffinized and DNA was extracted. Quantitative detection of MCPyV large T antigen was performed by absolute quantitative Real-Time PCR., Result: MCPyV DNA was detected in 30.6% (n: 11/36) of IF, 24.1% (n; 7/29) of OLP, 21.4% (n:3/14) of dysplasia and 20% (n;7/35) of OSCC samples. The mean MCPyV DNA copy number was 2.32×10-2 ± 3.97 ×10-2, 2.02×10-2 (SD=3.13×10-2), 2.69×10-4 (SD=2.51×10-4), and 2.56×10-4 (SD=6.73×10-4) per cell in OSCC, dysplasia and both of OLP and OIF samples, respectively (P=0.76)., Conclusion: This study provides the first data from Iran regarding the presence of MCPyV genome in oral cavity lesions and oral cancer. These results also emphasize that MCPyV has an active role in the occurrence of oral lesions and progression to cancer. Further studies should be carried out to clarify the role of MCPyV in oral cavity lesions.

Merkel cell polyomavirus (MCPyV) viral protein 1 (VP1) is the capsid protein that mediates virus attachment to host cell receptors and is the major immune target. Given the limited data on MCPyV VP1 mutations, the VP1 genetic variability was examined in 100 plasma and 100 urine samples from 100 HIV+ individuals. Sequencing of VP1 DNA in 17 urine and 17 plasma specimens, simultaneously MCPyV DNA positive, revealed that 27 samples displayed sequences identical to VP1 of MCC350 strain. VP1 from two urine specimens had either Thr47Ser or Ile115Phe substitution, whereas VP1 of one plasma contained Asp69Val and Ser251Phe substitutions plus deletion (∆) of Tyr79. VP1 DNA in the remaining samples had mutations encoding truncated protein. Three-dimensional prediction models revealed that Asp69Val, Ser251Phe, and Ile115Phe caused neutral effects while Thr47Ser and Tyr79∆ produced a deleterious effect reducing VP1 stability. A549 cells infected with urine or plasma samples containing full-length VP1 variants with substitutions, sustained viral DNA replication and VP1 expression. Moreover, medium harvested from these cells was able to infect new A549 cells. In cells infected by samples with truncated VP1, MCPyV replication was hampered. In conclusion, MCPyV strains with unique mutations in the VP1 gene are circulating in HIV+ patients. These strains display altered replication efficiency compared to the MCC350 prototype strain in A549 cells. [ABSTRACT FROM AUTHOR]

Background: Viral infections of the anal/rectal tract of men who have sex with men (MSM) have been poorly studied. Methods: In total, 158 swab samples (81 anal/rectal, 65 throat/oral and 12 urethral) were collected from 126 MSM. DNA was isolated and subjected to real-time PCR assays for the detection of the sexually transmitted (ST) pathogens Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasmas ssp, human papillomavirus (HPV) and six human polyomaviruses (HPyVs; JCPyV, BKPyV, Merkel cell PyV–MCPyV-, HPyV-6, HPyV-7 and HPyV-9). Results: C. trachomatis (31/126, 24.6%) and M. genitalium (30/126, 23.8%) were the most frequently detected ST pathogens. Thirty-one/126 (24.6%) patients were positive for at least one HPyV. The significantly (p < 0.05) prevalent HPyV in the anal tract was MCPyV, which was amplified in 27/81 (33.3%) samples, followed by HPyV-6, which was amplified in 6/81 (7.4%) swabs. Coinfections with MCPyV and C. trachomatis or Mycoplasmas were found in 4/21 (19.0%) and 5/21 (23.8%) anal/rectal swabs, respectively. Three/4 MCPyV-C. trachomatis coinfected patients were symptomatic. Conclusions: Based on the high prevalence of MCPyV in the anal/rectal swabs from MSM patients and on the well-known oncogenic properties of MCPyV, sexual transmission and possible involvement of HPyVs in the pathogenesis of diseases of the anal canal should be further studied. [ABSTRACT FROM AUTHOR]