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Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV-negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high-grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T-truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC-typical cellular origin for the combined MCC/neuroblastomas. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Antígenos Virais de Tumores , Carcinoma de Célula de Merkel , Transdiferenciação Celular , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/metabolismo , Masculino , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/metabolismo , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismo , Poliomavírus das Células de Merkel/genética , Pontos de Checagem do Ciclo Celular/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Idoso de 80 Anos ou mais , Idoso , Neoplasias Complexas Mistas/patologia , Neoplasias Complexas Mistas/genética , Neoplasias Complexas Mistas/metabolismo , Neuroblastoma/patologia , Neuroblastoma/genética , Neuroblastoma/metabolismoRESUMO
Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high mortality rate. Merkel cell polyomavirus causes 80% of MCCs, encoding the viral oncogenes small T and truncated large T (tLT) antigens. These proteins impair the RB1-dependent G1/S checkpoint blockade and subvert the host cell epigenome to promote cancer. Whole-proteome analysis and proximal interactomics identified a tLT-dependent deregulation of DNA damage response (DDR). Our investigation revealed, to our knowledge, a previously unreported interaction between tLT and the histone methyltransferase EHMT2. T antigen knockdown reduced DDR protein levels and increased the levels of the DNA damage marker γH2Ax. EHMT2 normally promotes H3K9 methylation and DDR signaling. Given that inhibition of EHMT2 did not significantly change the MCC cell proteome, tLT-EHMT2 interaction could affect the DDR. With tLT, we report that EHMT2 gained DNA damage repair proximal interactors. EHMT2 inhibition rescued proliferation in MCC cells depleted for their T antigens, suggesting impaired DDR and/or lack of checkpoint efficiency. Combined tLT and EHMT2 inhibition led to altered DDR, evidenced by multiple signaling alterations. In this study, we show that tLT hijacks multiple components of the DNA damage machinery to enhance tolerance to DNA damage in MCC cells, which could explain the genetic stability of these cancers.
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BACKGROUND: The limited therapies available for treating Merkel cell carcinoma (MCC), a highly aggressive skin neoplasm, still pose clinical challenges, and novel treatments are required. Targeting retinoid signalling with retinoids, such as all-trans retinoic acid (ATRA), is a promising and clinically useful antitumor approach. ATRA drives tumour cell differentiation by modulating retinoid signalling, leading to anti-proliferative and pro-apoptotic effects. Although retinoid signalling is dysregulated in MCC, ATRA activity in this tumour is unknown. This study aimed to evaluate the impact of ATRA on the pathological phenotype of MCC cells. METHODS: The effect of ATRA was tested in various Merkel cell polyomavirus-positive and polyomavirus-negative MCC cell lines in terms of cell proliferation, viability, migration and clonogenic abilities. In addition, cell cycle, apoptosis/cell death and the retinoid gene signature were evaluated upon ATRA treatments. RESULTS: ATRA efficiently impaired MCC cell proliferation and viability in MCC cells. A strong effect in reducing cell migration and clonogenicity was determined in ATRA-treated cells. Moreover, ATRA resulted as strongly effective in arresting cell cycle and inducing apoptosis/cell death in all tested MCC cells. Enrichment analyses indicated that ATRA was effective in modulating the retinoid gene signature in MCC cells to promote cell differentiation pathways, which led to anti-proliferative and pro-apoptotic/cell death effects. CONCLUSIONS: These results underline the potential of retinoid-based therapy for MCC management and might open the way to novel experimental approaches with other retinoids and/or combinatorial treatments.
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Apoptose , Carcinoma de Célula de Merkel , Diferenciação Celular , Proliferação de Células , Neoplasias Cutâneas , Tretinoína , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/metabolismo , Carcinoma de Célula de Merkel/patologia , Humanos , Proliferação de Células/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Retinoides/farmacologia , Retinoides/uso terapêutico , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacosRESUMO
AIMS: Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV). Characteristic for these virus-positive (VP) MCC is MCPyV integration into the host genome and truncation of the viral oncogene Large T antigen (LT), with full-length LT expression considered as incompatible with MCC growth. Genetic analysis of a VP-MCC/trichoblastoma combined tumour demonstrated that virus-driven MCC can arise from an epithelial cell. Here we describe two further cases of VP-MCC combined with an adnexal tumour, i.e. one trichoblastoma and one poroma. METHODS AND RESULTS: Whole-genome sequencing of MCC/trichoblastoma again provided evidence of a trichoblastoma-derived MCC. Although an MCC-typical LT-truncating mutation was detected, we could not determine an integration site and we additionally detected a wildtype sequence encoding full-length LT. Similarly, Sanger sequencing of the combined MCC/poroma revealed coding sequences for both truncated and full-length LT. Moreover, in situ RNA hybridization demonstrated expression of a late region mRNA encoding the viral capsid protein VP1 in both combined as well as in a few cases of pure MCC. CONCLUSION: The data presented here suggest the presence of wildtype MCPyV genomes and VP1 transcription in a subset of MCC.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Poroma , Neoplasias Cutâneas , Neoplasias das Glândulas Sudoríparas , Humanos , Carcinoma de Célula de Merkel/metabolismo , Poliomavírus das Células de Merkel/genética , Infecções por Polyomavirus/complicações , Neoplasias Cutâneas/patologia , GenômicaRESUMO
INTRODUCTION: Immunosuppressive drugs taken by transplant recipients may favor HPV infection at anogenital sites. HPV-type prevalence was studied in males and females before and after renal transplantation. PATIENTS AND METHODS: Anal, cervical and penile samples were taken from 62 patients before transplantation and from 41 patients after transplantation. HPV DNA was investigated using the INNO-LiPA HPV genotyping extra test and HPV-type distribution determined. RESULTS: Before transplantation, up to 30% of analyzed samples harbored HPV DNA, with the highest prevalence found in cervical specimens (60%). After transplantation, a trend toward HPV clearance was observed in females. By contrast, a trend toward incident infections by a wide variety of HPV genotypes at the penis and anal level was documented in men. CONCLUSION: High prevalence of HPV at anogenital sites was documented before and after renal transplantation. Immunosuppressive drugs taken after transplantation may impact HPV acquisition or reactivation, especially in males. Special attention should be paid in view of preventing HPV-associated diseases in this vulnerable population.
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Transplante de Rim , Infecções por Papillomavirus , Masculino , Humanos , Feminino , Infecções por Papillomavirus/epidemiologia , Transplante de Rim/efeitos adversos , Papillomaviridae/genética , DNARESUMO
Digital papillary adenocarcinoma (DPA) is a rare sweat gland neoplasm that has exceptionally been reported outside acral locations. Recently, human papillomavirus 42 was identified as the main oncogenic driver of DPA. Herein, we report 5 tumors arising in extra-acral locations predominantly in the female anogenital skin. Four patients were female and 1 patient was male. The mean age at the diagnosis time was 65 years (range: 55 to 82 y). Tumors were located on the vulva (n=3), perianal area (n=1), and forearm (n=1). Histologically, all tumors were lobular and mainly solid and composed of sheets of cells with rare focal papillae and frequent glandular structures in a "back-to-back" pattern and lined by atypical basophilic cells. Immunohistochemistry showed diffuse positivity for SOX10. Epithelial membrane antigen and carcinoembryonic antigen highlighted the luminal cells and staining for p63 and p40 revealed a consistent and continuous myoepithelial component around glandular structures. Follow-up was available in 3 cases (mean duration: 12 mo [range: 8 to 16 mo]). One patient developed local recurrence and 1 experienced regional lymph node metastases. HPV Capture Next-generation sequencing revealed the presence of the HPV42 genome in all samples. Viral reads distributions were compatible in the 5 cases with an episomal nature of the viral genome, with a recurrent deletion in the E1 and/or E2 open reading frames. In conclusion, this study demonstrates that digital DPA may rarely present in nonacral locations mainly in the female anogenital area, usually with a more solid pattern as compared with those cases presenting on the digits and it is also associated with HPV42.
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Adenocarcinoma Papilar , Neoplasias Ósseas , Neoplasias da Mama , Neoplasias de Tecido Conjuntivo , Neoplasias das Glândulas Sudoríparas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias das Glândulas Sudoríparas/química , Biomarcadores Tumorais/genética , Adenocarcinoma Papilar/patologiaRESUMO
Recurrent oncogenic drivers have been identified in a variety of sweat gland tumors. Recently, integration of human papillomavirus type 42 (HPV42) has been reported in digital papillary adenocarcinoma (DPA). The main objectives of the present study were (i) to provide an overview of the prevalence of previously identified oncogenic drivers in acral sweat gland tumors and (ii) to genetically characterize tumors in which no recurrent genetic alteration has been identified yet. Cases of acral sweat gland tumors were identified from the database of the French network CARADERM. After histologic review, the presence of previously identified genetic alterations was investigated in the entire cohort (n=79) using a combination of immunohistochemistry and targeted DNA and RNA sequencing. Tumor entities with no recurrent genetic alterations were submitted to whole-transcriptome sequencing. CRTC1::MAML2 fusion was identified in cases of hidradenoma and hidradenocarcinoma (n=9/12 and n=9/12). A p.V600E mutation of BRAF was observed in all cases of tubular adenoma (n=4). YAP1:MAML2 and YAP1::NUTM1 fusions were observed in poroid tumors (n=15/25). ETV6::NTRK3 and TRPS1::PLAG1 fusion transcripts were identified in secretory carcinoma (n=1/1) and cutaneous mixed tumors (n=3/4), respectively. The HPV42 genome was detected in most cases of DPA (n=10/11) and in 1 adnexal adenocarcinoma not otherwise specified. Finally, whole-transcriptome analysis revealed BRD3::NUTM1 or NSD3::NUTM1 fusions in 2 cases of NUT adnexal carcinoma and NCOA4::RET and CCDC6::RET fusion transcripts in 2 cystadenoma/hidrocystoma-like tumors. Our study confirms distinctive cytogenetic abnormalities in a wide number of acral adnexal neoplasms and supports the use of molecular analysis as a valuable aid in the diagnosis of these rare and often difficult to diagnose group of neoplasms.
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Acrospiroma , Adenocarcinoma Papilar , Carcinoma , Neoplasias Cutâneas , Neoplasias das Glândulas Sudoríparas , Humanos , Neoplasias das Glândulas Sudoríparas/química , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Acrospiroma/patologia , Fatores de Transcrição/genética , Adenocarcinoma Papilar/patologia , Proteínas RepressorasRESUMO
Limited molecular knowledge of Merkel cell polyomavirus (MCPyV)-positive and -negative Merkel cell carcinoma (MCC) subsets (MCCP/MCCN) has prevented so far the identification of the MCC origin cell type and, therefore, the development of effective therapies. The retinoic gene signature was investigated in various MCCP, MCCN, and control fibroblast/epithelial cell lines to elucidate the heterogeneous nature of MCC. Hierarchical clustering and principal component analysis indicated that MCCP and MCCN cells were clusterizable from each other and control cells, according to their retinoic gene signature. MCCP versus MCCN differentially expressed genes (n = 43) were identified. Protein-protein interaction network indicated SOX2, ISL1, PAX6, FGF8, ASCL1, OLIG2, SHH, and GLI1 as upregulated hub genes and JAG1 and MYC as downregulated hub genes in MCCP compared to MCCN. Numerous MCCP-associated hub genes were DNA-binding/-transcription factors involved in neurological and Merkel cell development and stemness. Enrichment analyses indicated that MCCP versus MCCN differentially expressed genes predominantly encode for to DNA-binding/-transcription factors involved in development, stemness, invasiveness, and cancer. Our findings suggest the neuroendocrine origin of MCCP, by which neuronal precursor cells could undergo an MCPyV-driven transformation. These overarching results might open the way to novel retinoid-based MCC therapies.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/genética , Poliomavírus das Células de Merkel/genética , Fatores de Transcrição/genética , DNARESUMO
Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus-positive than virus-negative tumors (P = 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/patologia , Histonas/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias Cutâneas/patologia , Poliomavírus das Células de Merkel/genética , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismoRESUMO
Lichen planus (LP) is a cutaneomucosal chronic inflammatory disease characterized by a CD8+ cytotoxic T-lymphocytes (CTL) infiltrate. In erosive oral LP, we found HPV16-specific activated CTL in lesions, supporting a pathogenic contribution of HPV16. Here, we investigated whether a similar scenario occurs in other clinical forms of LP and in lichen sclerosus et atrophicus (LSA), another chronic disease also affecting the mucosa and/or the skin. Blood CTL from LP and LSA patients expressed significant higher levels of granzyme B, perforin and CD107a proteins than healthy donors. Expansions of TCRVß3+ CTL, with presence of TCR clonotypes identical to those previously detected in erosive oral LP, were found both in blood and mucosal/skin lesions of LP, and not of LSA patients. These expansions were enriched with HPV16-specific CD8+ T-cells as shown by their recognition of the E711-20 immunodominant epitope. In LSA patients, the peripheral repertoire of CTL was oligoclonal for TCRVß6+ CTL. Finally, although patients with LP and LSA have developed antibodies against HPV16 capsid L1, antibodies against HPV16 E6 were only observed in patients with LP. Overall, our data collectively suggest an involvement of HPV16-specific CTL in different clinical forms of LP, not only in erosive oral LP, while a different scenario operates in LSA.
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Líquen Plano Bucal , Líquen Plano , Líquen Escleroso e Atrófico , Humanos , Papillomavirus Humano , Linfócitos T CD8-Positivos/metabolismo , Papillomavirus Humano 16 , Líquen Escleroso e Atrófico/metabolismo , Líquen Escleroso e Atrófico/patologia , Líquen Plano/patologiaRESUMO
AIMS: Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, and the diagnostic use of YAP1 immunohistochemistry has been highlighted in this setting. In other organs, loss of YAP1 expression can reflect YAP1 rearrangement or transcriptional repression, notably through RB1 inactivation. In this context, our objective was to re-evaluate the performance of YAP1 immunohistochemistry for the diagnosis of poroma and porocarcinoma. METHODS AND RESULTS: The expression of the C-terminal part of the YAP1 protein was evaluated by immunohistochemistry in 543 cutaneous epithelial tumours, including 27 poromas, 14 porocarcinomas and 502 other cutaneous tumours. Tumours that showed a lack of expression of YAP1 were further investigated for Rb by immunohistochemistry and for fusion transcripts by real-time PCR (YAP1::MAML2 and YAP1::NUTM1). The absence of YAP1 expression was observed in 24 cases of poroma (89%), 10 porocarcinoma (72%), 162 Merkel cell carcinoma (98%), 14 squamous cell carcinoma (SCC) (15%), one trichoblastoma and one sebaceoma. Fusions of YAP1 were detected in only 16 cases of poroma (n = 66%), 10 porocarcinoma (71%) all lacking YAP1 expression, and in one sebaceoma. The loss of Rb expression was detected in all cases except one of YAP1-deficient SCC (n = 14), such tumours showing significant morphological overlap with porocarcinoma. In-vitro experiments in HaCat cells showed that RB1 knockdown resulted in repression of YAP1 protein expression. CONCLUSION: In addition to gene fusion, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including MCC and a subset of SCC.
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Carcinoma , Porocarcinoma Écrino , Poroma , Neoplasias Cutâneas , Neoplasias das Glândulas Sudoríparas , Humanos , Poroma/genética , Poroma/metabolismo , Poroma/patologia , Neoplasias das Glândulas Sudoríparas/diagnóstico , Porocarcinoma Écrino/genética , Porocarcinoma Écrino/patologia , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas de Ligação a Retinoblastoma/metabolismoRESUMO
Merkel cell carcinoma (MCC) is an aggressive skin malignancy with two distinct etiologies. The first, which accounts for the highest proportion, is caused by Merkel cell polyomavirus (MCPyV), a DNA tumor virus. A second, UV-induced, MCC form has also been identified. Few MCC diagnostic, prognostic, and therapeutic options are available. MicroRNAs (miRNAs) are small noncoding RNA molecules, which play a key role in regulating various physiologic cellular functions including cell cycling, proliferation, differentiation, and apoptosis. Numerous miRNAs are dysregulated in cancer, by acting as either tumor suppressors or oncomiRs. The aim of this review is to collect, summarize, and discuss recent findings on miRNAs whose dysregulation has been assumed to play a role in MCC. The potential clinical application of miRNAs as diagnostic and prognostic biomarkers in MCC is also described. In the future, miRNAs will potentially gain clinical significance for the improvement of MCC diagnostic, prognostic, and therapeutic options.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , MicroRNAs , Infecções por Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Humanos , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/genética , MicroRNAs/genética , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/genética , Infecções Tumorais por Vírus/diagnóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Poliomavírus das Células de Merkel/genéticaRESUMO
The incidence of oropharyngeal cancers (OPC) is increasing in the world. Among OPC, those induced by human papillomaviruses have a better prognosis than non-HPV-associated OPC. The objective of this study was to highlight the relevance of HPV16 load, HPV16 DNA integration and HPV16-L1 serology on progression-free survival and overall survival of OPC patients. The PAPILLOPHAR cohort consists of 362 patients with oropharyngeal squamous cell carcinomas prospectively followed up for 5 years after treatment. Tumor biopsies and sera were collected at inclusion to investigate tumor HPV DNA/RNA characteristics and HPV16 L1 serology, respectively. Twenty-seven percent of tumor biopsies were HPV DNA- and RNA-positive and HPV16 represented 93% of HPV-positive cases. Among them, neither HPV16 viral load nor HPV16 DNA integration was associated with overall survival (OS) or progression-free survival (PFS). In contrast, high anti-HPV16 L1 antibody titers were significantly associated with a better OS and PFS. This study reveals that HPV16 load and integration are not relevant prognosis biomarkers in OPC patients.Clinical Relevance: High levels of HPV16 L1 antibodies may be useful to predict OPC patient outcome following treatment.ClinicalTrials.gov Identifier: NCT00918710, May 2017.
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Papillomavirus Humano 16 , Neoplasias Orofaríngeas , Humanos , Papillomavirus Humano 16/genética , Anticorpos Antivirais , Neoplasias Orofaríngeas/patologia , Prognóstico , DNA Viral/genéticaRESUMO
Introduction: Human polyomaviruses (HPyVs) cause persistent/latent infections in a large fraction of the population. HPyV infections may cause severe diseases in immunocompromised patients. Malawi polyomavirus (MWPyV) is the 10th discovered human polyomavirus (HPyV 10). MWPyV was found in stool samples of healthy children. So far, the few investigations carried out on HPyV 10 did not find an association with human disease. Methods: In this study, to verify the putative association between MWPyV and human diseases, MWPyV seroprevalence was investigated in patients affected by i) lymphoproliferative disorders (LPDs) and ii) immune system disorders, i.e., autoimmune diseases (ADs), and in iii) healthy subjects. An indirect ELISA, employing virus-like particles (VLPs) to detect serum IgG antibodies against MWPyV/HPyV 10, was carried out. The study also revealed the prevalence of another polyomavirus, Merkel cell polyomavirus (MCPyV). Results: Sera from patients with distinct autoimmune diseases (n = 44; mean age 20 years) had a prevalence of MWPyV antibodies of 68%, while in patients with lymphoproliferative disorders (n = 15; mean age 14 years), subjected to bone marrow transplantation, the prevalence was 47%. In healthy subjects (n = 66; mean age 13 years), the prevalence of MWPyV antibodies was 67%. Our immunological investigation indicates that MWPyV/HPyV 10 seroconversion occurs early in life and MWPyV/HPyV 10 appears to be another polyomavirus ubiquitous in the human population. A significantly lower MWPyV antibody reactivity together with a lower immunological profile was detected in the sera of LPD patients compared with HS2 (*p < 0.05) (Fisher's exact test). LPD and AD patients have a similar MCPyV seroprevalence compared with healthy subjects. Discussion: MWPyV seroprevalence indicates that this HPyV is not associated with lymphoproliferative and autoimmune diseases. However, the ability to produce high levels of antibodies against MWPyV appears to be impaired in patients with lymphoproliferative disorders. Immunological investigations indicate that MWPyV seroconversion occurs early in life. MCPyV appears to be a ubiquitous polyomavirus, like other HPyVs, in the human population.
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Doenças Autoimunes , Transtornos Linfoproliferativos , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Polyomavirus , Criança , Humanos , Adulto Jovem , Adulto , Adolescente , Imunoglobulina G , Prevalência , Transplante de Medula Óssea , Estudos Soroepidemiológicos , Malaui/epidemiologia , Transtornos Linfoproliferativos/epidemiologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/complicaçõesRESUMO
MCC (Merkel cell carcinoma) is an aggressive neuroendocrine cutaneous neoplasm. Integration of the Merkel cell polyomavirus (MCPyV) is observed in about 80% of the cases, while the remaining 20% are related to UV exposure. Both MCPyV-positive and -negative MCCs-albeit by different mechanisms-are associated with RB1 inactivation leading to overexpression of SOX2, a major contributor to MCC biology. Moreover, although controversial, loss of RB1 expression seems to be restricted to MCPyV-negative cases.The aim of the present study was to assess the performances of RB1 loss and SOX2 expression detected by immunohistochemistry to determine MCPyV status and to diagnose MCC, respectively.Overall, 196 MCC tumors, 233 non-neuroendocrine skin neoplasms and 70 extra-cutaneous neuroendocrine carcinomas (NEC) were included. SOX2 and RB1 expressions were assessed by immunohistochemistry in a tissue micro-array. Diagnostic performances were determined using the likelihood ratio (LHR).RB1 expression loss was evidenced in 27% of the MCC cases, 12% of non-neuroendocrine skin tumors and 63% of extra-cutaneous NEC. Importantly, among MCC cases, RB1 loss was detected in all MCPyV(-) MCCs, while MCPyV( +) cases were consistently RB1-positive (p < 0.001). SOX2 diffuse expression was observed in 92% of the MCC cases and almost never observed in non-neuroendocrine skin epithelial neoplasms (2%, p < 0.0001, LHR + = 59). Furthermore, SOX2 diffuse staining was more frequently observed in MCCs than in extra-cutaneous NECs (30%, p < 0.001, LHR + = 3.1).These results confirm RB1 as a robust predictor of MCC viral status and further suggest SOX2 to be a relevant diagnostic marker of MCC.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/patologia , Humanos , Poliomavírus das Células de Merkel/metabolismo , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/metabolismo , Proteínas de Ligação a Retinoblastoma , Fatores de Transcrição SOXB1/metabolismo , Neoplasias Cutâneas/patologia , Infecções Tumorais por Vírus/complicações , Ubiquitina-Proteína LigasesRESUMO
Merkel Cell Carcinoma (MCC) is a rare but highly aggressive form of non-melanoma skin cancer whose 5-year survival rate is 63%. Merkel cell polyomavirus (MCPyV), a small DNA tumor virus, is the etiological agent of MCC. Although representing a small proportion of MCC cases, MCPyV-negative MCCs have also been identified. The role of epigenetic mechanisms, including histone post-translational modifications (PTMs) in MCC, have been only partially determined. This review aims to describe the most recent progress on PTMs and their regulative factors in the context of MCC onset/development, providing an overview of current findings on both MCC subtypes. An outline of current knowledge on the potential employment of PTMs and related factors as diagnostic and prognostic markers, as well as novel treatment strategies targeting the reversibility of PTMs for MCC therapy is provided. Recent research shows that PTMs are emerging as important epigenetic players involved in MCC onset/development, and therefore may show a potential clinical significance. Deeper and integrated knowledge of currently known PTM dysregulations is of paramount importance in order to understand the molecular basis of MCC and improve the diagnosis, prognosis, and therapeutic options for this deadly tumor.