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Shirzadi A, Bajelan B, Mohammadifard F, Ahmadinejad M, Bagherpour JZ. Metastatic Merkel cell carcinoma with an unknown primary tumor presenting as lymphadenopathy: A case report. Int J Surg Case Rep 2025; 131:111382. [PMID: 40378421 PMCID: PMC12145708 DOI: 10.1016/j.ijscr.2025.111382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 04/24/2025] [Accepted: 04/26/2025] [Indexed: 05/18/2025] Open
Abstract
INTRODUCTION AND IMPORTANCE Merkel cell carcinoma is one of the rare neuroendocrine tumors of the skin. Neuroendocrine nodal MCCUP is a rare and poorly understood malignancy. In this article, we introduce a case of MCCUP with primary manifestation of lymphadenopathy. CASE PRESENTATION A 62-year-old woman presented with lymphadenopathy in the inguinal region, and the diagnosis of metastatic Merkel cell carcinoma was made in the excisional biopsy. The primary source of the tumor was not found in the imaging workup and the patient underwent lymphadenectomy. CLINICAL DISCUSSION MCCUP is a rare subtype of MCC, with specific diagnostic criteria. Most MCCs are symptom-free, requiring biopsy for confirmation. NE tumor marker analysis is crucial for distinguishing NE carcinoma, with CK20 and another NE marker sufficient for MCCUP diagnosis. LCA is not found in MCC tumors, and Ki-67 is used for prognosis. Treatment includes surgery, radiotherapy, and sometimes chemotherapy, although its efficacy is debated. CONCLUSION MCCUP is a rare disease affecting primarily elderly, several treatment regimens have been considered for the treatment of this rare tumor. One of the treatments with good results can be extensive surgery and patient follow-up.
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Affiliation(s)
- Alireza Shirzadi
- Non-Communicable Disease Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Bahar Bajelan
- School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Mojtaba Ahmadinejad
- Department of General Surgery, Alborz University of Medical Sciences, Karaj, Iran
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Yeni Erdem B, Baykal C, Ozluk Y, Ahmed MA, Kozanoglu E, Saip P, Buyukbabani N, Ozturk Sari S. Evaluating CK20 and MCPyV Antibody Clones in Diagnosing Merkel Cell Carcinoma. Endocr Pathol 2025; 36:1. [PMID: 39841326 PMCID: PMC11754318 DOI: 10.1007/s12022-024-09845-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/29/2024] [Indexed: 01/23/2025]
Abstract
Merkel cell carcinoma (MCC) is diagnosed through histopathological and immunohistochemical examination of biopsies from skin or other organs. Its distinguishing features include perinuclear dot-like staining with Cytokeratin 20 (CK20) and detection of Merkel cell polyomavirus (MCPyV) using various methods. However, CK20 and MCPyV negative MCC cases have been reported at varying rates. In this single center cross-sectional study, we aimed to determine which clones are more effective in diagnosing MCC by comparing the performance of CK20 antibody clones Ks20.8 and SP33, as well as MCPyV antibody clones Ab3 and CM2B4. Fifty-four patients diagnosed with MCC were included. Among these, 42 cases were primary cutaneous, and 12 cases were nodal MCC. Fifty-two (96.3%) cases were positive with both CK20 clones, while two cases were negative. Clone SP33 stained areas of necrosis, whereas Ks20.8 showed no aberrant staining. MCPyV was detected in 44 cases (81.5%) using clone Ab3 and 39 cases (72.2%) using clone CM2B4. Staining with MCPyV clone Ab3 was diffuse and strong in most cases, while approximately 30% of CM2B4-positive cases exhibited low percentages and/or weak staining, complicating the evaluation. The two CK20-negative cases were also negative with both MCPyV clones. Our data demonstrated that CK20 clone Ks20.8 may be preferred for MCC diagnosis due to its consistent performance and lack of aberrant staining. Similarly, MCPyV clone Ab3 appears superior to CM2B4 for identifying MCPyV-positive cases.
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Affiliation(s)
- Begum Yeni Erdem
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Fatih, Istanbul, 34093, Turkey
| | - Can Baykal
- Department of Dermatology and Venereology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Fatih, Istanbul, 34093, Turkey
| | - Yasemin Ozluk
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Fatih, Istanbul, 34093, Turkey
| | - Melin A Ahmed
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Millet Caddesi, Fatih, Istanbul, 34093, Turkey
| | - Erol Kozanoglu
- Department of Plastic, Reconstructive and Aesthetic Surgery, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Fatih, Istanbul, 34093, Turkey
| | - Pinar Saip
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Millet Caddesi, Fatih, Istanbul, 34093, Turkey
| | - Nesimi Buyukbabani
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Fatih, Istanbul, 34093, Turkey
- Department of Pathology, Koc University Hospital, Davutpasa Caddesi, Zeytinburnu, Istanbul, 34010, Turkey
| | - Sule Ozturk Sari
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Millet Caddesi, Fatih, Istanbul, 34093, Turkey.
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Al-Shajrawi OM, Tarawneh IA, Tengku Din TADAADAA, Afolabi HA. The role of microalgal extracts and their combination with tamoxifen in the modulation of breast cancer immunotherapy (Review). Mol Clin Oncol 2025; 22:6. [PMID: 39559458 PMCID: PMC11570877 DOI: 10.3892/mco.2024.2801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/01/2024] [Indexed: 11/20/2024] Open
Abstract
Cancer is one of the deadliest health menaces humans have ever witnessed. It is a leading cause of human mortality. Today, it remains a main leading cause of death globally primarily due to lifestyle changes and population ageing. A total of ~12.7 million cancer cases and 7.6 million cancer deaths were reported in 2008. In developing countries, cancer accounted for 56% of cases and 64% of deaths. Tamoxifen is the most reputable and recommended specific oestrogen receptor modulator drug used for the treatment of breast cancer. In the past decade, algae have demonstrated remarkable potency for advanced life applications. They can remain a focus of interest in the coming decades because they are one of the most diverse organisms in the entire ecosystem with immense bio nutritional benefits. Algae and their extracts play a pivotal role in the pharmaceutical industry as bioactive compounds and new drugs and nutraceutical industry as probiotics and antioxidants. However, a broad range of the health benefits of these organisms remains to be explored. The present review highlights the applications and co-application of microalgal crude extracts with tamoxifen for breast cancer immunotherapy. Given that recent studies have suggested that tamoxifen is an essential and primary treatment for breast cancer, the present review focused on the identification of a new treatment approach involving the co-application of tamoxifen and microalgal extracts to provide promising anticancer activity with few side effects on normal cells. The present review includes a general background and blueprint for the use of microalgal extracts as potential and affordable treatments or adjuncts for breast cancer management.
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Affiliation(s)
- Omar Mahmoud Al-Shajrawi
- Department of Chemical Pathology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Kota Bharu, Kelantan 16150, Malaysia
| | - Ibraheam A.M. Tarawneh
- School of Graduate Studies, Management and Science University, Shah Alam, Selangor 40100, Malaysia
| | | | - Hafeez Abiola Afolabi
- Department of Pathology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Kota Bharu, Kelantan 16150, Malaysia
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Odeny TA, Fink V, Muchengeti M, Gopal S. Cancer in People with HIV. Infect Dis Clin North Am 2024; 38:531-557. [PMID: 39111924 PMCID: PMC11529824 DOI: 10.1016/j.idc.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
We review the intersection of human immunodeficiency virus (HIV) and cancer globally, including the complex interplay of oncogenic infections, chronic inflammation, and behavioral and other factors in increasing cancer risk among people with HIV (PWH). We discuss current cancer screening, prevention, and treatment recommendations for PWH. Specific interventions include vaccination, behavioral risk reduction, timely HIV diagnosis and treatment, screening for specific cancer sites, and multifaceted treatment considerations unique to PWH including supportive care and drug interactions. Finally, the potential of novel therapies and the need for inclusive cancer clinical trials are highlighted. Collaborative multidisciplinary efforts are critical for continued progress against cancer among PWH.
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Affiliation(s)
- Thomas A Odeny
- Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., CB 8056, St. Louis, MO 63110-1093, USA
| | - Valeria Fink
- Research Department, Fundación Huésped, Av. Forest 345 (C1427CEA) Buenos Aires, Argentina
| | - Mazvita Muchengeti
- School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; South African DSI-NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, South Africa
| | - Satish Gopal
- Center for Global Health, National Cancer Institute, 9609 Medical Center Drive, Rockville MD 20850, USA.
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Myrda J, Bremm F, Schaft N, Dörrie J. The Role of the Large T Antigen in the Molecular Pathogenesis of Merkel Cell Carcinoma. Genes (Basel) 2024; 15:1127. [PMID: 39336718 PMCID: PMC11431464 DOI: 10.3390/genes15091127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
The large T antigen (LT) of the Merkel cell polyomavirus (MCPyV) is crucial for Merkel cell carcinoma (MCC), a rare but very aggressive form of neuroendocrine skin cancer. The clonal integration of MCPyV DNA into the host genome is a signature event of this malignancy. The resulting expression of oncogenes, including the small T (sT) antigen and a truncated form of the LT (truncLT), directly contribute to carcinogenesis. The truncation of the C-terminus of LT prevents the virus from replicating due to the loss of the origin binding domain (OBD) and the helicase domain. This precludes cytopathic effects that would lead to DNA damage and ultimately cell death. At the same time, the LxCxE motif in the N-terminus is retained, allowing truncLT to bind the retinoblastoma protein (pRb), a cellular tumor suppressor. The continuously inactivated pRb promotes cell proliferation and tumor development. truncLT exerts several classical functions of an oncogene: altering the host cell cycle, suppressing innate immune responses to viral DNA, causing immune escape, and shifting metabolism in favor of cancer cells. Given its central role in MCC, the LT is a major target for therapeutic interventions with novel approaches, such as immune checkpoint inhibition, T cell-based immunotherapy, and cancer vaccines.
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Affiliation(s)
- Julia Myrda
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Franziska Bremm
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Niels Schaft
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Jan Dörrie
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
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Mubeen A, Mito JK. The diagnostic utility of Merkel cell polyoma virus immunohistochemistry in cytology specimens. Cytopathology 2024; 35:390-397. [PMID: 38353321 DOI: 10.1111/cyt.13366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 01/29/2024] [Indexed: 04/09/2024]
Abstract
OBJECTIVE Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine neoplasm that predominantly affects elderly and immunocompromised patients. Merkel cell polyoma virus (MCPyV) is clonally integrated into the majority of MCCs and has been linked to patient outcomes, playing a central role in the pathogenesis of the disease. We aimed to assess the utility of MCPyV immunohistochemistry (IHC) in the diagnosis of MCC in cytology cell block specimens and correlating with clinicopathologic features. METHODS Fifty-three cytology samples of MCC with sufficient cell block material were stained for MCPyV by IHC and scored semi-quantitatively in extent and intensity. Morphologic mimics of MCC including small cell lung carcinoma (n = 10), non-Hodgkin lymphoma (n = 10), basaloid squamous cell carcinoma (n = 6) and other neuroendocrine carcinomas (n = 8) were stained in parallel. Positive staining was defined as >1% of the tumour cells showing at least moderate staining intensity. RESULTS The cytologic features of MCC were characterized by high nuclear-cytoplasmic ratios, hyperchromatic nuclei with 'salt and pepper' chromatin, and nuclear moulding. MCPyV was detected in 24 of 53 cases (45%). Staining was strong and diffuse in roughly half of the positive samples. Of the morphologic mimics, one follicular lymphoma showed strong and diffuse staining. In contrast to prior studies, we saw no association between MCPyV status and patient outcomes. CONCLUSION Merkel cell polyoma virus IHC is highly specific (97%) for the diagnosis of MCC in our cohort, and can serve as a useful diagnostic tool for distinguishing MCC for morphologic mimics.
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Affiliation(s)
- Aysha Mubeen
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Department of Pathology, The University of New Mexico, Albuquerque, New Mexico, USA
| | - Jeffrey K Mito
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
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Zilberg C, Ferguson AL, Lyons JG, Gupta R, Fuller SJ, Damian DL. Cutaneous malignancies in chronic lymphocytic leukemia. J Dermatol 2024; 51:353-364. [PMID: 38291978 DOI: 10.1111/1346-8138.17126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/28/2023] [Accepted: 01/04/2024] [Indexed: 02/01/2024]
Abstract
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy that is associated with an increased risk of developing cutaneous malignancies. Clinical outcomes for these malignancies, including melanoma and keratinocyte cancers (KC), are worse for patients with CLL. Individuals with CLL develop an immunodeficiency of both the adaptive and innate immune system, which plays a role in the increased prevalence of skin cancers. This review focuses on the complex interplay between genetics, immunity, and pathogens that influence the cellular composition and biology of skin tumors and their microenvironment in CLL patients, and in comparison with other chronic hematological malignancies. It is paramount for dermatologists to be aware of the association between CLL (and chronic hematological malignancies more broadly) and cutaneous malignancies. This is a high-risk population who require regular and vigorous dermatologic follow-up.
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Affiliation(s)
- Catherine Zilberg
- Department of Dermatology, The University of Sydney at Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
- Melanoma Institute Australia, Wollstonecraft, New South Wales, Australia
| | - Angela L Ferguson
- Centenary Institute, The University of Sydney, Camperdown, New South Wales, Australia
| | - James G Lyons
- Department of Dermatology, The University of Sydney at Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
- Centenary Institute, The University of Sydney, Camperdown, New South Wales, Australia
| | - Ruta Gupta
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, NSW Health Pathology, Camperdown, New South Wales, Australia
| | - Stephen J Fuller
- Sydney Medical School, Nepean Clinical School, The Faculty of Medicine and Health, The University of Sydney, Kingswood, New South Wales, Australia
- Nepean Hospital, Kingswood, New South Wales, Australia
| | - Diona L Damian
- Department of Dermatology, The University of Sydney at Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
- Melanoma Institute Australia, Wollstonecraft, New South Wales, Australia
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8
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Ryu H, Bi TM, Pulliam TH, Sarkar K, Church CD, Kumar N, Mayer-Blackwell K, Jani S, Ramchurren N, Hansen UK, Hadrup SR, Fling SP, Koelle DM, Nghiem P, Newell EW. Merkel cell polyomavirus-specific and CD39 +CLA + CD8 T cells as blood-based predictive biomarkers for PD-1 blockade in Merkel cell carcinoma. Cell Rep Med 2024; 5:101390. [PMID: 38340724 PMCID: PMC10897544 DOI: 10.1016/j.xcrm.2023.101390] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 11/29/2023] [Accepted: 12/21/2023] [Indexed: 02/12/2024]
Abstract
Merkel cell carcinoma is a skin cancer often driven by Merkel cell polyomavirus (MCPyV) with high rates of response to anti-PD-1 therapy despite low mutational burden. MCPyV-specific CD8 T cells are implicated in anti-PD-1-associated immune responses and provide a means to directly study tumor-specific T cell responses to treatment. Using mass cytometry and combinatorial tetramer staining, we find that baseline frequencies of blood MCPyV-specific cells correlated with response and survival. Frequencies of these cells decrease markedly during response to therapy. Phenotypes of MCPyV-specific CD8 T cells have distinct expression patterns of CD39, cutaneous lymphocyte-associated antigen (CLA), and CD103. Correspondingly, overall bulk CD39+CLA+ CD8 T cell frequencies in blood correlate with MCPyV-specific cell frequencies and similarly predicted favorable clinical outcomes. Conversely, frequencies of CD39+CD103+ CD8 T cells are associated with tumor burden and worse outcomes. These cell subsets can be useful as biomarkers and to isolate blood-derived tumor-specific T cells.
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Affiliation(s)
- Heeju Ryu
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Timothy M Bi
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Thomas H Pulliam
- Department of Medicine, Division of Dermatology, University of Washington, Seattle, WA, USA
| | - Korok Sarkar
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Candice D Church
- Department of Medicine, Division of Dermatology, University of Washington, Seattle, WA, USA
| | - Nandita Kumar
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Lab Medicine and Pathology, University of Washington, Seattle, WA, USA
| | | | - Saumya Jani
- Department of Medicine, Division of Dermatology, University of Washington, Seattle, WA, USA; Department of Lab Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Nirasha Ramchurren
- Cancer Immunotherapy Trails Network, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Ulla K Hansen
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Sine R Hadrup
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Steven P Fling
- Cancer Immunotherapy Trails Network, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - David M Koelle
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Lab Medicine and Pathology, University of Washington, Seattle, WA, USA; Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA; Benaroya Research Institute, Seattle, WA, USA
| | - Paul Nghiem
- Department of Medicine, Division of Dermatology, University of Washington, Seattle, WA, USA
| | - Evan W Newell
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Lab Medicine and Pathology, University of Washington, Seattle, WA, USA.
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Gaur P, Rajak N, Tiwari A, Kumar P, Garg N. Role of microRNAs in oncogenic viral infection diagnosis and therapeutics. MICRORNA IN HUMAN INFECTIOUS DISEASES 2024:179-200. [DOI: 10.1016/b978-0-323-99661-7.00005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Khattri M, Amako Y, Gibbs JR, Collura JL, Arora R, Harold A, Li MY, Harms PW, Ezhkova E, Shuda M. Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus. Tumour Virus Res 2023; 16:200264. [PMID: 37244352 PMCID: PMC10258072 DOI: 10.1016/j.tvr.2023.200264] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/19/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023] Open
Abstract
Merkel cell polyomavirus (MCV) and high-risk human papillomavirus (HPV) are human tumor viruses that cause Merkel cell carcinoma (MCC) and oropharyngeal squamous cell carcinoma (OSCC), respectively. HPV E7 and MCV large T (LT) oncoproteins target the retinoblastoma tumor suppressor protein (pRb) through the conserved LxCxE motif. We identified enhancer of zeste homolog 2 (EZH2) as a common host oncoprotein activated by both viral oncoproteins through the pRb binding motif. EZH2 is a catalytic subunit of the polycomb 2 (PRC2) complex that trimethylates histone H3 at lysine 27 (H3K27me3). In MCC tissues EZH2 was highly expressed, irrespective of MCV status. Loss-of-function studies revealed that viral HPV E6/E7 and T antigen expression are required for Ezh2 mRNA expression and that EZH2 is essential for HPV(+)OSCC and MCV(+)MCC cell growth. Furthermore, EZH2 protein degraders reduced cell viability efficiently and rapidly in HPV(+)OSCC and MCV(+)MCC cells, whereas EZH2 histone methyltransferase inhibitors did not affect cell proliferation or viability within the same treatment period. These results suggest that a methyltransferase-independent function of EZH2 contributes to tumorigenesis downstream of two viral oncoproteins, and that direct targeting of EZH2 protein expression could be a promising strategy for the inhibition of tumor growth in HPV(+)OSCC and MCV(+)MCC patients.
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Affiliation(s)
- Michelle Khattri
- Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Yutaka Amako
- Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Julia R Gibbs
- Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Joseph L Collura
- Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Reety Arora
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
| | - Alexis Harold
- Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Meng Yen Li
- Developmental and Regenerative Biology, Mt. Sinai School of Medicine, New York, NY, USA; Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, 10029, USA
| | - Paul W Harms
- Departments of Pathology and Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Elena Ezhkova
- Developmental and Regenerative Biology, Mt. Sinai School of Medicine, New York, NY, USA; Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, 10029, USA
| | - Masahiro Shuda
- Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
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Lawrence L, Wang A, Charville G, Liu CL, Garofalo A, Alizadeh A, Jangam D, Pinsky BA, Sahoo M, Gratzinger D, Khodadoust M, Kim Y, Novoa R, Stehr H. Identification and confirmation via in situ hybridization of Merkel cell polyomavirus in rare cases of posttransplant cutaneous T-cell lymphoma. J Cutan Pathol 2023; 50:835-844. [PMID: 37394808 DOI: 10.1111/cup.14486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 05/25/2023] [Accepted: 06/06/2023] [Indexed: 07/04/2023]
Abstract
BACKGROUND Viral infection is an oncogenic factor in many hematolymphoid malignancies. We sought to determine the diagnostic yield of aligning off-target reads incidentally obtained during targeted hematolymphoid next-generation sequencing to a large database of viral genomes to screen for viral sequences within tumor specimens. METHODS Alignment of off-target reads to viral genomes was performed using magicBLAST. Localization of Merkel cell polyomavirus (MCPyV) RNA was confirmed by RNAScope in situ hybridization. Integration analysis was performed using Virus-Clip. RESULTS Four cases of post-cardiac-transplant folliculotropic mycosis fungoides (fMF) and one case of peripheral T-cell lymphoma (PTCL) were positive in off-target reads for MCPyV DNA. Two of the four cases of posttransplant fMF and the case of PTCL showed localization of MCPyV RNA to malignant lymphocytes, whereas the remaining two cases of posttransplant fMF showed MCPyV RNA in keratinocytes. CONCLUSIONS Our findings raise the question of whether MCPyV may play a role in rare cases of T-lymphoproliferative disorders, particularly in the skin and in the heavily immunosuppressed posttransplant setting.
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Affiliation(s)
| | - Aihui Wang
- Stanford University School of Medicine, Stanford, California, USA
| | | | - Chih Long Liu
- Stanford University School of Medicine, Stanford, California, USA
| | - Andrea Garofalo
- Stanford University School of Medicine, Stanford, California, USA
| | - Ash Alizadeh
- Stanford University School of Medicine, Stanford, California, USA
| | | | | | - Malaya Sahoo
- Stanford University School of Medicine, Stanford, California, USA
| | - Dita Gratzinger
- Stanford University School of Medicine, Stanford, California, USA
| | | | - Youn Kim
- Stanford University School of Medicine, Stanford, California, USA
| | - Roberto Novoa
- Stanford University School of Medicine, Stanford, California, USA
| | - Henning Stehr
- Stanford University School of Medicine, Stanford, California, USA
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Rossi RE, Corti F, Pusceddu S, Milione M, Coppa J, Masoni B, Oldani S, Sabella G, Cafaro P, Repici A. Multidisciplinary Approach to the Diagnosis of Occult Primary Neuroendocrine Neoplasm: A Clinical Challenge. J Clin Med 2023; 12:5537. [PMID: 37685605 PMCID: PMC10488469 DOI: 10.3390/jcm12175537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/31/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Approximately 11% to 14% of subjects with neuroendocrine neoplasms (NENs) have metastatic lesions with unknown primary origin (UPO), with the majority of UPO-NENs found in the small bowel. Herein, we assessed the available literature on UPO-NENs, focusing on clinical presentation and diagnostic techniques to identify the primary site. The identification of the primary tumor is important as it affects the prognosis; however, the clinical presentation can be non-specific in non-functioning forms. In the presence of metastatic disease, the histological sample is fundamental to obtain immunohistochemical markers that might orientate the clinician in the search for the primary tumor through radiology, functional imaging and endoscopic techniques. In summary, multidisciplinary management plays a key role in UPO-NENs, even more than in other NENs. Molecular biology and gene-expression profiling represent areas of great interest which might be developed in the near future for both the diagnosis and the treatment of these neoplasms.
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Affiliation(s)
- Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (B.M.); (A.R.)
| | - Francesca Corti
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori Monza, Via G.B. Pergolesi, 20900 Monza, Italy; (F.C.); (P.C.)
| | - Sara Pusceddu
- Gastro-Entero-Pancreatic and Neuroendocrine Tumor Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Massimo Milione
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS–Istituto Nazionale dei Tumori, 20133 Milan, Italy; (M.M.); (G.S.)
| | - Jorgelina Coppa
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy;
| | - Benedetta Masoni
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (B.M.); (A.R.)
| | - Simone Oldani
- Gastro-Entero-Pancreatic and Neuroendocrine Tumor Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Giovanna Sabella
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS–Istituto Nazionale dei Tumori, 20133 Milan, Italy; (M.M.); (G.S.)
| | - Pietro Cafaro
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori Monza, Via G.B. Pergolesi, 20900 Monza, Italy; (F.C.); (P.C.)
| | - Alessandro Repici
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (B.M.); (A.R.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
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Quantification of human polyomaviruses MCPyV and HPyV6 in malignant and non-malignant skin lesions. An Bras Dermatol 2023; 98:198-201. [PMID: 36635157 PMCID: PMC9984872 DOI: 10.1016/j.abd.2022.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/10/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Human Polyomaviruses such as MCPyV and HPyV6 are frequently found as part of healthy skin microbiota and have been associated with Merkel cell carcinoma (MCC), pruritic and dyskeratotic dermatoses, respectively. Their presence in other types of skin conditions varies greatly depending on lesion type and population. OBJECTIVE To analyse comparatively the presence of MCPyV and HPyV6 in nonmelanoma skin cancers and healthy skin. METHODS The authors utilized qPCR techniques to quantify these pathogens in NMSC, premalignant diseases, and healthy skin of 87 patients. RESULTS MCPyV was detected in over 40% of samples, while HPyV6 was in 9.6%. MCPyV load was higher in squamous cell carcinomas (SCC) compared to basal cell carcinomas (BCC) (p=0.016) and HPyV6 showed a higher percentage of infected cells in areas of low solar exposure as well as normal skin (p=0.012). A fair agreement (kappa=0.301) was found between MCPyV detection in lesions and their respective perilesional skin, indicating a random process of local dissemination of the virus. STUDY LIMITATIONS The lack of a larger sampling of different lesion types and protein expression analyses limits the correlation findings. CONCLUSION This is the first report of HPyV6 detection in the healthy skin of a Brazilian population, but the role of both polyomaviruses in NMSC has yet to be demonstrated.
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Silling S, Kreuter A, Gambichler T, Meyer T, Stockfleth E, Wieland U. Epidemiology of Merkel Cell Polyomavirus Infection and Merkel Cell Carcinoma. Cancers (Basel) 2022; 14:6176. [PMID: 36551657 PMCID: PMC9776808 DOI: 10.3390/cancers14246176] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/06/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
Merkel cell polyomavirus (MCPyV) is a ubiquitous virus replicating in human dermal fibroblasts. MCPyV DNA can be detected on healthy skin in 67−90% of various body sites, and intact virions are regularly shed from the skin. Infection occurs early in life, and seropositivity increases from 37 to 42% in 1- to 6-year-olds to 92% in adults. Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine tumor of the skin. It develops mainly on sun-exposed areas as a fast-growing, reddish nodule. Two MCC entities exist: about 80% of MCC are MCPyV-associated. Tumorigenesis is driven by viral integration into the host genome and MCPyV oncogene expression. In MCPyV-negative MCC, UV radiation causes extensive DNA damage leading to the deregulation of the cell cycle. In recent decades, MCC incidence rates have increased worldwide, e.g., in the United States, from 0.15 in 1986 to 0.7/100,000 in 2016. Risk factors for the development of MCC include male sex, older age (>75 years), fair skin, intense UV exposure, and immunosuppression. Projections suggest that due to aging populations, an increase in immunosuppressed patients, and enhanced UV exposure, MCC incidence rates will continue to rise. Early diagnosis and prompt treatment are crucial to reducing high MCC morbidity and mortality.
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Affiliation(s)
- Steffi Silling
- Institute of Virology, National Reference Center for Papilloma- and Polyomaviruses, Faculty of Medicine, University Hospital Cologne, 50935 Cologne, Germany
| | - Alexander Kreuter
- Department of Dermatology, Venereology and Allergology, HELIOS St. Elisabeth Hospital Oberhausen, University Witten/Herdecke, 58455 Witten, Germany
| | - Thilo Gambichler
- Skin Cancer Center, Department of Dermatology, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Thomas Meyer
- Skin Cancer Center, Department of Dermatology, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Eggert Stockfleth
- Skin Cancer Center, Department of Dermatology, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Ulrike Wieland
- Institute of Virology, National Reference Center for Papilloma- and Polyomaviruses, Faculty of Medicine, University Hospital Cologne, 50935 Cologne, Germany
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15
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Komatsu H, Usui Y, Sukeda A, Yamamoto Y, Ohno SI, Goto K, Kuroda M, Nagao T, Goto H. Prevalence of Merkel Cell Polyomavirus in Primary Eyelid Merkel Cell Carcinomas and Association With Clinicopathological Features. Am J Ophthalmol 2022; 249:49-56. [PMID: 36493850 DOI: 10.1016/j.ajo.2022.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 11/10/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE Merkel cell polyomavirus (MCPyV) infection is a known to be a critical risk factor for the development of Merkel cell carcinoma (MCC). Various reports on cutaneous MCC have shown that the differences in clinicohistopathological characteristics depend on the presence of MCPyV, but the situation in eyelid MCC is unknown. This study aimed to assess the prevalence of MCPyV in patients with eyelid MCC and examine the clinicohistopathological characteristics of MCPyV-associated eyelid MCC. DESIGN Retrospective observational case series with laboratory investigations. METHODS Ten patients treated for eyelid MCC were included. Histopathological characteristics were examined by immunohistochemical staining using 12 antibodies. MCPyV infection was evaluated by PCR using primer sets targeting large T antigens of the MCPyV genome and by immunohistochemical staining using CM2B4 and Ab3 monoclonal antibodies. The MCPyV viral load was also quantified by PCR using 3 primer sets. RESULTS All patients (4 males and 6 females) were Japanese with mean age of 79 (range: 63 to 87) years. One patient died due to distant metastasis 8 months after surgery for MCC. Immunohistochemical studies showed typical MCC findings in all cases, including CK20 and neuroendocrine marker positivity. PCR and immunohistochemistry with CM2B4 and Ab3 detected MCPyV antigen in all tumors. Quantitative PCR using sT, LT4, and TAg primers yielded 0.94, 1.72, and 1.05 copies per cell, respectively. CONCLUSION Clinical and histopathological characteristics of 10 patients with eyelid MCC were elucidated. MCPyV infection was detected in all eyelids. These results provide insight for understanding the tumorigenesis of eyelid MCC.
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Affiliation(s)
- Hiroyuki Komatsu
- From the Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan (H.K., Y.U., H.G.)
| | - Yoshihiko Usui
- From the Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan (H.K., Y.U., H.G.).
| | - Aoi Sukeda
- Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan (A.S., Y.Y., K.G., T.N.)
| | - Yoshinari Yamamoto
- Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan (A.S., Y.Y., K.G., T.N.)
| | - Shin-Ichiro Ohno
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan (S I. O., M.K.)
| | - Keisuke Goto
- Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan (A.S., Y.Y., K.G., T.N.)
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan (S I. O., M.K.)
| | - Toshitaka Nagao
- Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan (A.S., Y.Y., K.G., T.N.)
| | - Hiroshi Goto
- From the Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan (H.K., Y.U., H.G.)
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Hasanzadeh A, Sadeghi F, Kamrani G, Mohammadi N, Vosough Z, Ranaee M, Tabarraei A, Yahyapour Y. Quantitative analysis of Merkel cell polyomavirus (MCPyV) genome in non-melanoma skin cancer and normal tumor margins. Braz J Microbiol 2022; 53:1987-1994. [PMID: 36279096 PMCID: PMC9679045 DOI: 10.1007/s42770-022-00850-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 10/12/2022] [Indexed: 01/13/2023] Open
Abstract
Merkel cell polyomavirus (MCPyV) is the cause of approximately 80% of Merkel cell carcinomas (MCC). The common types of non-melanoma skin cancer (NMSC) including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are histologically similar to MCC. In the present study, 58 NMSC formalin-fixed paraffin-embedded tissue (FFPE) samples including 12 SCC, 46 BCC, and 58 FFPE samples of adjacent non-tumoral margins as the control were included. Determination of large tumor antigens (LTAg) copy number was performed by qReal-Time PCR as a viral copy number per cell to elucidate MCPyV carcinogenic role in non-melanoma skin cancer. Out of 58 samples, 36 (62%) cancerous and 22 (37.9%) normal tumor margins were positive for MCPyV LTAg. Median copy numbers of MCPyV LTAg among all NMSC samples and non-tumoral margins were 0.308×10-2 and 0.269×10-3 copies per cell respectively (P=0.001). In addition, although the viral load in the majority of samples was detected to be lower than one copy per cell, in 4 BCC samples, a viral load higher than one LTAg copy per cell was detected. The present study revealed that the detection of higher levels of MCPyV LTAg viral load in some BCC and SCC samples may be correlated with the role of MCPyV in some cases of BCC and SCC skin cancer.
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Affiliation(s)
- Ali Hasanzadeh
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Farzin Sadeghi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ghodsieh Kamrani
- Department of Pathology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Neda Mohammadi
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Vosough
- Department of Pathology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Ranaee
- Department of Pathology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Alijan Tabarraei
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Yousef Yahyapour
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
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Akaike T, Cahill K, Akaike G, Huynh ET, Hippe DS, Shinohara MM, Liao J, Apisarnthanarax S, Parvathaneni U, Hall E, Bhatia S, Cheng RK, Nghiem P, Tseng YD. Management and Prognosis of Cardiac Metastatic Merkel Cell Carcinoma: A Case-Control Study and Literature Review. Cancers (Basel) 2022; 14:5914. [PMID: 36497395 PMCID: PMC9741306 DOI: 10.3390/cancers14235914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/18/2022] [Accepted: 11/23/2022] [Indexed: 12/03/2022] Open
Abstract
Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin cancer, has a high rate (20%) of distant metastasis. Within a prospective registry of 582 patients with metastatic MCC (mMCC) diagnosed between 2003-2021, we identified 9 (1.5%) patients who developed cardiac metastatic MCC (mMCC). We compared overall survival (OS) between patients with cardiac and non-cardiac metastases in a matched case-control study. Cardiac metastasis was a late event (median 925 days from initial MCC diagnosis). The right heart was predominantly involved (8 of 9; 89%). Among 7 patients treated with immunotherapy, 6 achieved a complete or partial response of the cardiac lesion. Among these 6 responders, 5 received concurrent cardiac radiotherapy (median 20 Gray) with immunotherapy; 4 of 5 did not have local disease progression or recurrence in the treated cardiac lesion. One-year OS was 44%, which was not significantly different from non-cardiac mMCC patients (45%, p = 0.96). Though it occurs relatively late in the disease course, cardiac mMCC responded to immunotherapy and/or radiotherapy and was not associated with worse prognosis compared to mMCC at other anatomic sites. These results are timely as cardiac mMCC may be increasingly encountered in the era of immunotherapy as patients with metastatic MCC live longer.
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Affiliation(s)
- Tomoko Akaike
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Kelsey Cahill
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Gensuke Akaike
- Department of Radiology, University of Washington, Seattle, WA 98195, USA
- TRA Medical Imaging, Tacoma, WA 98402, USA
| | - Emily T. Huynh
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Daniel S. Hippe
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | - Michi M. Shinohara
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Jay Liao
- Department of Radiation Oncology, University of Washington, Seattle, WA 91895, USA
| | | | - Upendra Parvathaneni
- Department of Radiation Oncology, University of Washington, Seattle, WA 91895, USA
| | - Evan Hall
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Shailender Bhatia
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Richard K. Cheng
- Division of Cardiology, University of Washington Medical Center, Seattle, WA 98195, USA
| | - Paul Nghiem
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | - Yolanda D. Tseng
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Department of Radiation Oncology, University of Washington, Seattle, WA 91895, USA
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18
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Dimitraki MG, Sourvinos G. Merkel Cell Polyomavirus (MCPyV) and Cancers: Emergency Bell or False Alarm? Cancers (Basel) 2022; 14:cancers14225548. [PMID: 36428641 PMCID: PMC9688650 DOI: 10.3390/cancers14225548] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/06/2022] [Accepted: 11/08/2022] [Indexed: 11/15/2022] Open
Abstract
Merkel cell polyomavirus (MCPyV), the sole member of Polyomavirus associated with oncogenesis in humans, is the major causative factor of Merkel cell carcinoma (MCC), a rare, neuroendocrine neoplasia of the skin. Many aspects of MCPyV biology and oncogenic mechanisms remain poorly understood. However, it has been established that oncogenic transformation is the outcome of the integration of the viral genome into the host DNA. The high prevalence of MCPyV in the population, along with the detection of the virus in various human tissue samples and the strong association of MCPyV with the emergence of MCC, have prompted researchers to further investigate the role of MCPyV in malignancies other than MCC. MCPyV DNA has been detected in several different non-MCC tumour tissues but with significantly lower prevalence, viral load and protein expression. Moreover, the two hallmarks of MCPyV MCC have rarely been investigated and the studies have produced generally inconsistent results. Therefore, the outcomes of the studies are inadequate and unable to clearly demonstrate a direct correlation between cellular transformation and MCPyV. This review aims to present a comprehensive recapitulation of the available literature regarding the association of MCPyV with oncogenesis (MCC and non-MCC tumours).
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19
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Ferrándiz‐Pulido C, Gómez‐Tomás A, Llombart B, Mendoza D, Marcoval J, Piaserico S, Baykal C, Bouwes‐Bavinck J, Rácz E, Kanitakis J, Harwood C, Cetkovská P, Geusau A, del Marmol V, Masferrer E, Orte Cano C, Ricar J, de Oliveira W, Salido‐Vallejo R, Ducroux E, Gkini M, López‐Guerrero J, Kutzner H, Kempf W, Seçkin D. Clinicopathological features, MCPyV status and outcomes of Merkel cell carcinoma in solid-organ transplant recipients: a retrospective, multicentre cohort study. J Eur Acad Dermatol Venereol 2022; 36:1991-2001. [PMID: 35607918 PMCID: PMC9796956 DOI: 10.1111/jdv.18256] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 04/13/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND The proportion of Merkel cell carcinomas (MCCs) in solid-organ transplant recipients (SOTR) harbouring Merkel cell polyomavirus (MCPyV) is unknown, as are factors affecting their outcomes. OBJECTIVE To describe clinicopathological features of MCC in SOTR, investigate the tumoral MCPyV-status and identify factors associated with tumour outcomes. METHODS Retrospective, international, cohort-study. MCPyV-status was investigated by immunohistochemistry and polymerase chain reaction. RESULTS A total of 30 SOTR and 44 consecutive immunocompetent patients with MCC were enrolled. SOTR were younger at diagnosis (69 vs. 78 years, P < 0.001). Thirty-three percent of SOTR MCCs were MCPyV-positive vs. 91% of immunocompetent MCCs (P = 0.001). Solid-organ transplantation was associated with an increased cumulative incidence of progression (SHR: 3.35 [1.57-7.14], P = 0.002), MCC-specific mortality (SHR: 2.55 [1.07-6.06], P = 0.034) and overall mortality (HR: 3.26 [1.54-6.9], P = 0.002). MCPyV-positivity and switching to an mTOR inhibitor (mTORi) after MCC diagnosis were associated with an increased incidence of progression (SHR: 4.3 [1.5-13], P = 0.008 and SHR: 3.6 [1.1-12], P = 0.032 respectively) in SOTR. LIMITATIONS Retrospective design and heterogeneity of SOTR cohort. CONCLUSIONS MCPyV appears to play a less prominent role in the aetiopathogenesis of MCC in SOTR. SOTR have a worse prognosis than their immunocompetent counterparts and switching to an mTORi after the diagnosis of MCC does not improve progression.
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Affiliation(s)
- C. Ferrándiz‐Pulido
- Department of DermatologyHospital Universitari Vall d'Hebron, Universitat Autònoma de BarcelonaBarcelonaSpain
| | - A. Gómez‐Tomás
- Department of DermatologyHospital Universitari Vall d'Hebron, Universitat Autònoma de BarcelonaBarcelonaSpain
| | - B. Llombart
- Servicio de DermatologíaInstituto Valenciano de OncologíaValenciaSpain
| | - D. Mendoza
- Department of DermatologyFundación Jiménez DíazMadridSpain
| | - J. Marcoval
- Department of DermatologyHospital de Bellvitge, IDIBELL, University of BarcelonaBarcelonaSpain
| | - S. Piaserico
- Dermatology Unit, Department of MedicineUniversità di PadovaPadovaItaly
| | - C. Baykal
- Department of DermatologyIstanbul University, Istanbul Medical FacultyIstanbulTurkey
| | - J.N. Bouwes‐Bavinck
- Department of DermatologyLeiden University Medical CenterLeidenThe Netherlands
| | - E. Rácz
- Department of DermatologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - J. Kanitakis
- Department of DermatologyEdouard Herriot Hospital Group, Hospices Civils de LyonLyonFrance
| | - C.A. Harwood
- Centre for Cell Biology and Cutaneous ResearchBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of LondonLondonUK
| | - P. Cetkovská
- Department of DermatovenereologyFaculty of Medicine, Charles UniversityPilsenThe Czech Republic
| | - A. Geusau
- Department of DermatologyMedical University of ViennaViennaAustria
| | - V. del Marmol
- Service de DermatologieHôpital Erasme, Université Libre de BruxellesBrusselsBelgium
| | - E. Masferrer
- Department of DermatologyHospital Universitari Mútua de TerrassaBarcelonaSpain
| | - C. Orte Cano
- Service de DermatologieHôpital Erasme, Université Libre de BruxellesBrusselsBelgium
| | - J. Ricar
- Department of DermatovenereologyFaculty of Medicine, Charles UniversityPilsenThe Czech Republic
| | | | - R. Salido‐Vallejo
- Department of DermatologyUniversity Clinic of Navarra, School of Medicine, University of NavarraPamplonaSpain
| | - E. Ducroux
- Department of DermatologyEdouard Herriot Hospital Group, Hospices Civils de LyonLyonFrance
| | - M.A. Gkini
- Centre for Cell Biology and Cutaneous ResearchBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of LondonLondonUK
| | - J.A. López‐Guerrero
- Laboratory of Molecular BiologyFundación Instituto Valenciano de OncologíaValenciaSpain,IVO‐CIPF Joint Research Unit of Cancer, Príncipe Felipe Research Center (CIPF)ValenciaSpain,Department of PathologySchool of Medicine, Catholic University of Valencia ‘San Vicente Martir’ValenciaSpain
| | | | - W. Kempf
- Kempf und Pfaltz Histologische Diagnostik and Department of DermatologyUniversity Hospital ZurichZürichSwitzerland
| | - D. Seçkin
- Department of DermatologyBaşkent University Faculty of MedicineAnkaraTurkey
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20
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Loke ASW, Lambert PF, Spurgeon ME. Current In Vitro and In Vivo Models to Study MCPyV-Associated MCC. Viruses 2022; 14:2204. [PMID: 36298759 PMCID: PMC9607385 DOI: 10.3390/v14102204] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/01/2022] [Accepted: 10/02/2022] [Indexed: 11/06/2022] Open
Abstract
Merkel cell polyomavirus (MCPyV) is the only human polyomavirus currently known to cause human cancer. MCPyV is believed to be an etiological factor in at least 80% of cases of the rare but aggressive skin malignancy Merkel cell carcinoma (MCC). In these MCPyV+ MCC tumors, clonal integration of the viral genome results in the continued expression of two viral proteins: the viral small T antigen (ST) and a truncated form of the viral large T antigen. The oncogenic potential of MCPyV and the functional properties of the viral T antigens that contribute to neoplasia are becoming increasingly well-characterized with the recent development of model systems that recapitulate the biology of MCPyV+ MCC. In this review, we summarize our understanding of MCPyV and its role in MCC, followed by the current state of both in vitro and in vivo model systems used to study MCPyV and its contribution to carcinogenesis. We also highlight the remaining challenges within the field and the major considerations related to the ongoing development of in vitro and in vivo models of MCPyV+ MCC.
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Affiliation(s)
| | | | - Megan E. Spurgeon
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine & Public Health, University of Wisconsin, Madison, WI 53705, USA
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21
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Dataset for the Reporting of Merkel Cell Carcinoma: Recommendations From the International Collaboration on Cancer Reporting (ICCR). Am J Surg Pathol 2022; 46:1583-1591. [PMID: 36001458 DOI: 10.1097/pas.0000000000001959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Accurate and complete pathology reports are critical for the optimal management of cancer patients. Protocols for the pathologic reporting of Merkel cell carcinoma (MCC) have been developed independently by the Royal College of Pathologists (UK) and the College of American Pathologists. In this study, data elements for pathologic reporting of MCC were analyzed by an international panel of pathologists and clinicians with the aim of developing a common, internationally agreed upon dataset useful for clinical practice. The International Collaboration on Cancer Reporting expert review panel developed a protocol containing "core" (required) and "noncore" (recommended) elements. Core elements were defined as those that had evidentiary support and were unanimously agreed upon by the review panel as essential for the clinical management, staging, and/or assessment of prognosis in patients with MCC. Noncore elements were those considered to be clinical of interest, but with lesser degrees of supportive evidence or nonactionable implications. Ten core data elements for pathology reports on primary MCC were defined. Development and agreement on this evidence-based protocol at an international level was accomplished in a timely and efficient manner. The template developed for melanoma reporting was used as a structural base for this initiative. It is applicable to, and may facilitate the development of, protocols for other tumor types. Widespread utilization of an internationally agreed upon structured pathology dataset for MCC can be expected to lead to improved patient management. It should also facilitate collaborative clinical research.
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22
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Yang JF, You J. Merkel cell polyomavirus and associated Merkel cell carcinoma. Tumour Virus Res 2022; 13:200232. [PMID: 34920178 PMCID: PMC8715208 DOI: 10.1016/j.tvr.2021.200232] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/08/2021] [Accepted: 12/13/2021] [Indexed: 12/22/2022] Open
Abstract
Merkel cell polyomavirus (MCPyV) is a ubiquitous skin infection that can cause Merkel cell carcinoma (MCC), a highly lethal form of skin cancer with a nearly 50% mortality rate. Since the discovery of MCPyV in 2008, great advances have been made to improve our understanding of how the viral encoded oncoproteins contribute to MCC oncogenesis. However, our knowledge of the MCPyV infectious life cycle and its oncogenic mechanisms are still incomplete. The incidence of MCC has tripled over the past two decades, but effective treatments are lacking. Only recently have there been major victories in combatting metastatic MCC with the application of PD-1 immune checkpoint blockade. Still, these immune-based therapies are not ideal for patients with a medical need to maintain systemic immune suppression. As such, a better understanding of MCPyV's oncogenic mechanisms is needed in order to develop more effective and targeted therapies against virus-associated MCC. In this review, we discuss current areas of interest for MCPyV and MCC research and the progress made in elucidating both the natural host of MCPyV infection and the cell of origin for MCC. We also highlight the remaining gaps in our knowledge on the transcriptional regulation of MCPyV, which may be key to understanding and targeting viral oncogenesis for developing future therapies.
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Affiliation(s)
- June F Yang
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6076, USA
| | - Jianxin You
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6076, USA.
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23
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Wang Y, Li Y, Liang X, Xin S, Yang L, Cao P, Jiang M, Xin Y, Zhang S, Yang Y, Lu J. The implications of cell-free DNAs derived from tumor viruses as biomarkers of associated cancers. J Med Virol 2022; 94:4677-4688. [PMID: 35652186 DOI: 10.1002/jmv.27903] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/16/2022] [Accepted: 05/31/2022] [Indexed: 11/09/2022]
Abstract
Cancer is still ranked as a leading cause of death according to estimates from the World Health Organization (WHO) and the strong link between tumor viruses and human cancers have been proved for almost six decades. Cell-free DNA (cfDNA) has drawn enormous attention for its dynamic, instant, and noninvasive advantages as one popular type of cancer biomarker. cfDNAs are mainly released from apoptotic cells and exosomes released from cancer cells, including those infected with viruses. Although cfDNAs are present at low concentrations in peripheral blood, they can reflect tumor load with high sensitivity. Considering the relevance of the tumor viruses to the associated cancers, cfDNAs derived from viruses may serve as good biomarkers for the early screening, diagnosis, and treatment monitoring. In this review, we summarize the methods and newly developed analytic techniques for the detection of cfDNAs from different body fluids, and discuss the implications of cfDNAs derived from different tumor viruses in the detection and treatment monitoring of virus-associated cancers. A better understanding of cfDNAs derived from tumor viruses may help formulate novel anti-tumoral strategies to decrease the burden of cancers that attributed to viruses. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yiwei Wang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Yanling Li
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Xinyu Liang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China
| | - Shuyu Xin
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Li Yang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Pengfei Cao
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China
| | - Mingjuan Jiang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Yujie Xin
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Senmiao Zhang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Yang Yang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Jianhong Lu
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China.,China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
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Metastatic Neuroendocrine Neoplasms of Unknown Primary: Clues from Pathology Workup. Cancers (Basel) 2022; 14:cancers14092210. [PMID: 35565339 PMCID: PMC9100271 DOI: 10.3390/cancers14092210] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/19/2022] [Accepted: 04/26/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary While most neuroendocrine neoplasms are indolent and slow-growing tumors, subsets of cases will spread beyond the tissue of origin. Given the rather slow progress, some lesions are incidentally discovered as metastatic deposits rather than primary masses. In these cases, a biopsy is often taken to allow the pathologist to identify the tumor type and possibly the primary tumor site via microscopic examination. In this review, the authors present a simplified guide on how to approach metastatic neuroendocrine tumors from a pathologist’s perspective. Abstract Neuroendocrine neoplasms (NENs) are diverse tumors arising in various anatomical locations and may therefore cause a variety of symptoms leading to their discovery. However, there are instances in which a NEN first presents clinically as a metastatic deposit, while the associated primary tumor is not easily identified using conventional imaging techniques because of small primary tumor sizes. In this setting (which is referred to as a “NEN of unknown primary”; NEN-UP), a tissue biopsy is often procured to allow the surgical pathologist to diagnose the metastatic lesion. If indeed a metastatic NEN-UP is found, several clues can be obtained from morphological assessment and immunohistochemical staining patterns that individually or in concert may help identify the primary tumor site. Herein, histological and auxiliary analyses of value in this context are discussed in order to aid the pathologist when encountering these lesions in clinical practice.
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25
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Silling S, Kreuter A, Wieland U. [Human polyomavirus-associated skin diseases]. Hautarzt 2022; 73:426-433. [PMID: 35482045 DOI: 10.1007/s00105-022-04993-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2022] [Indexed: 11/30/2022]
Abstract
Of the 15 currently known human polyomaviruses (HPyV), eight have been found on healthy skin. Merkel cell polyomavirus (MCPyV), HPyV6, HPyV7, and to a lesser extent Saint Louis polyomavirus (STLPyV) are considered part of the human cutaneous virome. The most important cutaneous polyomavirus, MCPyV, causes the majority of Merkel cell carcinomas (MCC). MCC is a rare but very aggressive malignant skin tumor that affects both immunocompetent and immunosuppressed patients. A steady increase in incidence rates of this skin tumor has been observed in recent decades. MCC occurs primarily on sunlight-exposed skin of fair-skinned individuals. Risk factors for MCC development include immunosuppression and advanced age. In immunocompromised individuals, primary infection with trichodysplasia spinulosa-associated polyomavirus (TSPyV) can cause the very rare skin disease trichodysplasia spinulosa (TS). Keratin spines (spicules), mainly in the center of the face, clinically characterize this disease. Skin lesions associated with further HPyV have been described exclusively in immunocompromised individuals. For HPyV6 and HPyV7, cases of epithelial proliferation and pruritic dyskeratotic dermatitis have been published. HPyV9 and New Jersey polyomavirus (NJPyV-13) were each found in different skin lesions of individual patients. The role of these polyomaviruses in the development of the skin lesions is still unclear.
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Affiliation(s)
- Steffi Silling
- Institut für Virologie, Nationales Referenzzentrum für Papillom- und Polyomaviren, Universitätsklinikum Köln und Universität zu Köln, Fürst-Pückler-Str. 56, 50935, Köln, Deutschland
| | - Alexander Kreuter
- Klinik für Dermatologie, Venerologie und Allergologie, HELIOS St. Elisabeth Klinik Oberhausen, Universität Witten/Herdecke, Oberhausen, Deutschland.,Klinik für Dermatologie, Venerologie und Allergologie, HELIOS St. Johannes Klinik Duisburg, Duisburg, Deutschland
| | - Ulrike Wieland
- Institut für Virologie, Nationales Referenzzentrum für Papillom- und Polyomaviren, Universitätsklinikum Köln und Universität zu Köln, Fürst-Pückler-Str. 56, 50935, Köln, Deutschland.
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26
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Liu B, Zhang Q, Wang J, Cao S, Zhou Z, Liu ZX, Cheng H. iCAV: an integrative database of cancer-associated viruses. Database (Oxford) 2021; 2021:6461900. [PMID: 34907423 PMCID: PMC8725190 DOI: 10.1093/database/baab079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 11/12/2021] [Accepted: 12/07/2021] [Indexed: 11/12/2022]
Abstract
To date, various studies have found that the occurrence of cancer may be related to viral
infections. Therefore, it is important to explore the relationship between viruses and
diseases. The International Agency for Research on Cancer has defined six types of viruses
as Class 1 human carcinogens, including Epstein–Barr virus, hepatitis C virus, hepatitis B
virus, human T-cell lymphotropic virus, human herpesvirus 8 and human papillomavirus,
while Merkel cell polyomavirus is classified as ‘probably carcinogenic to humans’ (Group
2A). Therefore, in-depth research on these viruses will help clarify their relationship
with diseases, and substantial efforts have been made to sequence their genomes. However,
there is no complete database documenting these cancer-associated viruses, and researchers
are not able to easily access and retrieve the published genomes. In this study, we
developed iCAV, a database that integrates the genomes of cancer-related viruses and the
corresponding phenotypes. We collected a total of 18 649 genome sequences from seven human
disease-related viruses, and each virus was further classified by the associated disease,
sample and country. iCAV is a comprehensive resource of cancer-associated viruses that
provides browse and download functions for viral genomes. Database URL: http://icav.omicsbio.info/
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Affiliation(s)
- Bo Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Qingfeng Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Jingou Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shumin Cao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Zhiyuan Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ze-Xian Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Han Cheng
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
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27
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Arroyave AJ, Lewis JM, Landry M, McLoughlin JM, Enomoto LM. Merkel Cell Polyomavirus Antibody Titer Predicts Recurrence-Free Survival. Ann Surg Oncol 2021; 29:1620-1626. [PMID: 34853942 DOI: 10.1245/s10434-021-11008-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/19/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Merkel cell polyomavirus (MCPyV) is associated with the development of Merkel cell carcinoma (MCC). Antibody (MCPyV-Ab) titers may have prognostic implications. This study evaluated the impact of the presence or absence of MCPyV-Ab on the 2-year overall survival (OS) and disease-free survival (DFS) of MCC patients. METHODS This single-center, IRB-approved, retrospective cohort study evaluated 51 adult patients with MCC from 2014 to 2021 using a prospectively maintained database. Patients were compared by MCPyV-Ab status, and Kaplan-Meier analysis was used to evaluate 2-year OS and DFS. RESULTS Of the 51 patients, 13 (25.4%) were seropositive, 41 (80.4%) underwent wide excision, 40 (80.0%) received radiotherapy, and 43 (84.3%) received multimodal therapy. The median follow-up period was 15.5 months (range 1-69.5 months). The median 2-year OS of the entire cohort was not reached. The median 2-year OS was not reached for either the seronegative or the seropositive patients. The difference in 2-year OS between the groups was not statistically significant (p = 0.37). Eight patients, all seronegative, were never rendered disease-free and were removed from recurrence analysis. The seropositive patients experienced no recurrences. Of the 30 seronegative patients, 9 (30.0%) experienced recurrence. The median 2-year DFS of the entire cohort was not reached. The median 2-year DFS of the seronegative group was 22.2 months. The 2-year DFS was not reached for the seropositive cohort. Seropositivity conferred a significantly better 2-year DFS than seronegativity (p = 0.04). CONCLUSION The MCPyV-Ab seropositive patients demonstrated improved 2-year DFS. The seropositive patients showed a strong trend toward improved 2-year OS, although the difference not statistically significant. This study substantiated the value of MCPyV-Ab assessment for MCC.
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Affiliation(s)
- Aaron J Arroyave
- Department of Surgery, University of Tennessee, UT Graduate School of Medicine, Knoxville, TN, USA
| | - James M Lewis
- University Surgical Oncology, University of Tennessee, Knoxville, TN, USA.,Department of Surgery, University of Tennessee, UT Graduate School of Medicine, Knoxville, TN, USA
| | - Miles Landry
- Martin Health Physician Group, Cleveland Clinic, Port St. Lucie, FL, USA
| | - James M McLoughlin
- University Surgical Oncology, University of Tennessee, Knoxville, TN, USA.,Department of Surgery, University of Tennessee, UT Graduate School of Medicine, Knoxville, TN, USA
| | - Laura M Enomoto
- University Surgical Oncology, University of Tennessee, Knoxville, TN, USA. .,Department of Surgery, University of Tennessee, UT Graduate School of Medicine, Knoxville, TN, USA.
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28
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Alvarez Orellana J, Kwun HJ, Artusi S, Chang Y, Moore PS. Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication. J Infect Dis 2021; 224:1160-1169. [PMID: 32060513 PMCID: PMC8514189 DOI: 10.1093/infdis/jiaa071] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/13/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Human polyomaviruses can reactivate in transplant patients, causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic, rash or trichodysplasia spinulosa. Sirolimus and related mechanistic target of rapamycin (mTOR) inhibitors are transplant immunosuppressants. It is unknown if they directly reactivate polyomavirus replication from latency beyond their general effects on immunosuppression. METHODS In vitro expression and turnover of large T (LT) proteins from BK virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) after drug treatment were determined by immunoblotting, proximity ligation, replicon DNA replication, and whole virus immunofluorescence assays. RESULTS mTOR inhibition increased LT protein expression for all 5 pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease in the S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and increase in virus replication for JCV, MCV, TSV, and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor tacrolimus, at levels routinely achieved in patients, resulted in a dose-dependent increase in viral DNA replication for BKV, MCV, and HPyV7. CONCLUSIONS mTOR inhibitors, at therapeutic levels, directly activate polyomavirus replication through a Skp2-dependent mechanism, revealing a proteostatic latency mechanism common to polyomaviruses. Modifying existing drug regimens for transplant patients with polyomavirus-associated diseases may reduce symptomatic polyomavirus replication while maintaining allograft-sparing immunosuppression.
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Affiliation(s)
- Jennifer Alvarez Orellana
- Cancer Virology Program, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Hyun Jin Kwun
- Cancer Virology Program, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Immunology, Pennsylvania State University, Hershey, Pennsylvania, USA
| | - Sara Artusi
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yuan Chang
- Cancer Virology Program, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Patrick S Moore
- Cancer Virology Program, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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29
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Zebardast A, Yahyapour Y, Majidi MS, Chehrazi M, Sadeghi F. Detection of Epstein-Barr virus encoded small RNA genes in oral squamous cell carcinoma and non-cancerous oral cavity samples. BMC Oral Health 2021; 21:502. [PMID: 34615503 PMCID: PMC8495909 DOI: 10.1186/s12903-021-01867-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 10/01/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Epstein-Barr Virus (EBV) is a human oncogenic virus that can lead to cancer in lymphoid and epithelial cells and is one of the hypothesized causes of oral cavity lesions including oral squamous cell carcinoma (OSCC), but the etiological association remains undetermined. The present investigation aimed to explore the EBV presence, viral load, and EBV-encoded small RNA (EBER) sequence variation in tissue samples of patients with OSCC and other oral cavity lesions including oral lichen planus (OLP), and oral irritation fibroma (OIF). METHODS In total, 88 oral cavity samples (23 with OSCC, 29 with OLP, and 36 with OIF diagnosis) were examined by Real-Time PCR technique and some of them were sequenced. RESULTS Viral EBER sequence was detected in 6 out of the 23 OSCC (31.4%), 6 out of the 29 OLP (20.7%), and 3 out of the 36 OIF cases (8.3%). The mean EBV copy number was higher in OSCC samples (1.2 × 10-2 ± 1.3 × 10-2 copies/cell) compared to OLP (2.2 × 10-3 ± 2.6 × 10-3 copies/cell) and OIF (2.4 × 10-4 ± 2.0 × 10-4 copies/cell) samples, although this difference was not statistically significant (P = 0.318). The EBER gene was amplified and sequenced in 5 OSCC, 3 OLP, and 2 OIF samples with high EBV viral load. One OSCC, two OLP, and two OIF isolates showed different nucleotide variations compared with EBV-WT and AG876 prototype sequences: C6834T, C6870T, C6981T, C7085T, C7085G, and C7094T. CONCLUSION In our study the presence of more than one genome copies per tumor cell indicates the possible role of EBV infection in oral cancers. However, more studies should be conducted to clarify the role of EBV in OSCC carcinogenesis.
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Affiliation(s)
- Arghavan Zebardast
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Yousef Yahyapour
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Seyed Majidi
- School of Dental Medicine, Oral Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Chehrazi
- Department of Biostatistics and Epidemiology, School of Public Health, Babol University of Medical Sciences, Babol, Iran
| | - Farzin Sadeghi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
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30
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Gujar H, Mehta A, Li HT, Tsai YC, Qiu X, Weisenberger DJ, Jasiulionis MG, In GK, Liang G. Characterizing DNA methylation signatures and their potential functional roles in Merkel cell carcinoma. Genome Med 2021; 13:130. [PMID: 34399838 PMCID: PMC8365948 DOI: 10.1186/s13073-021-00946-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 08/03/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with limited treatment possibilities. Merkel cell tumors display with neuroendocrine features and Merkel cell polyomavirus (MCPyV) infection in the majority (80%) of patients. Although loss of histone H3 lysine 27 trimethylation (H3K27me3) has been shown during MCC tumorigenesis, epigenetic dysregulation has largely been overlooked. METHODS We conducted global DNA methylation profiling of clinically annotated MCC primary tumors, metastatic skin tumors, metastatic lymph node tumors, paired normal tissues, and two human MCC cell lines using the Illumina Infinium EPIC DNA methylation BeadArray platform. RESULTS Significant differential DNA methylation patterns across the genome are revealed between the four tissue types, as well as based on MCPyV status. Furthermore, 964 genes directly regulated by promoter or gene body DNA methylation were identified with high enrichment in neuro-related pathways. Finally, our findings suggest that loss of H3K27me3 occupancy in MCC is attributed to KDM6B and EZHIP overexpression as a consequence of promoter DNA hypomethylation. CONCLUSIONS We have demonstrated specific DNA methylation patterns for primary MCC tumors, metastatic MCCs, and adjacent-normal tissues. We have also identified DNA methylation markers that not only show potential diagnostic or prognostic utility in MCC management, but also correlate with MCC tumorigenesis, MCPyV expression, neuroendocrine features, and H3K27me3 status. The identification of DNA methylation alterations in MCC supports the need for further studies to understand the clinical implications of epigenetic dysregulation and potential therapeutic targets in MCC.
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Affiliation(s)
- Hemant Gujar
- Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA
| | - Arjun Mehta
- Department of Biochemistry and Molecular Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA
| | - Hong-Tao Li
- Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA
| | - Yvonne C. Tsai
- Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA
| | - Xiangning Qiu
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Daniel J. Weisenberger
- Department of Biochemistry and Molecular Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA
| | - Miriam Galvonas Jasiulionis
- Department of Pharmacology, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo 669 5 andar, Vila Clementino, São Paulo, SP 04039032 Brazil
| | - Gino K. In
- Department of Dermatology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA
| | - Gangning Liang
- Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA
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31
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Meriläinen AS, Sihto H, Koljonen V. Merkel cell polyomavirus is a passenger virus in both poroma and porocarcinoma. J Cutan Pathol 2021; 49:49-54. [PMID: 34313332 DOI: 10.1111/cup.14109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Merkel cell polyomavirus (MCPyV) has been studied in several malignant and nonmalignant tissues. However, only in Merkel cell carcinoma (MCC) has the connection to tumorigenesis been established. Previously, eccrine porocarcinoma samples were shown to express MCPyV in the majority of samples. We aimed to examine MCPyV in porocarcinoma and poroma samples using MCC as the reference material. METHODS We analyzed 17 porocarcinoma and 50 poroma samples for the presence of MCPyV using LT antigen immunostaining and DNA detection methods. In addition, 180 MCC samples served as controls. RESULTS MCPyV LT antigen immunostaining was detected in 10% of poroma and 18% of porocarcinoma samples; on the other hand, it was present in 65% of MCC samples. MCPyV DNA was detected in only 10% of poroma and porocarcinoma samples compared with 96% of MCC samples. The viral DNA copy number in all MCPyV DNA-positive MCCs was at least 25 times higher than that in porocarcinoma or poroma samples with the highest MCPyV DNA-to-PTPRG ratio. CONCLUSIONS The low number of viral DNA copies in poroma and porocarcinoma samples, together with the negative LT expression of MCPyV DNA-positive tumors, indicates that MCPyV is simply a passenger virus rather than an oncogenic driver of porocarcinoma.
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Affiliation(s)
| | - Harri Sihto
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Virve Koljonen
- Department of Plastic Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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32
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Klufah F, Mobaraki G, Liu D, Alharbi RA, Kurz AK, Speel EJM, Winnepenninckx V, Zur Hausen A. Emerging role of human polyomaviruses 6 and 7 in human cancers. Infect Agent Cancer 2021; 16:35. [PMID: 34001216 PMCID: PMC8130262 DOI: 10.1186/s13027-021-00374-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Currently 12 human polyomaviruses (HPyVs) have been identified, 6 of which have been associated with human diseases, including cancer. The discovery of the Merkel cell polyomavirus and its role in the etiopathogenesis in the majority of Merkel cell carcinomas has drawn significant attention, also to other novel HPyVs. In 2010, HPyV6 and HPyV7 were identified in healthy skin swabs. Ever since it has been speculated that they might contribute to the etiopathogenesis of skin and non-cutaneous human cancers. MAIN BODY Here we comprehensively reviewed and summarized the current evidence potentially indicating an involvement of HPyV6 and HPyV7 in the etiopathogenesis of neoplastic human diseases. The seroprevalence of both HPyV6 and 7 is high in a normal population and increases with age. In skin cancer tissues, HPyV6- DNA was far more often prevalent than HPyV7 in contrast to cancers of other anatomic sites, in which HPyV7 DNA was more frequently detected. CONCLUSION It is remarkable to find that the detection rate of HPyV6-DNA in tissues of skin malignancies is higher than HPyV7-DNA and may indicate a role of HPyV6 in the etiopathogenesis of the respected skin cancers. However, the sheer presence of viral DNA is not enough to prove a role in the etiopathogenesis of these cancers.
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Affiliation(s)
- Faisal Klufah
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Ghalib Mobaraki
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Dan Liu
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Raed A Alharbi
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Anna Kordelia Kurz
- Department of Internal Medicine IV, RWTH Aachen University Hospital, Aachen, Germany
| | - Ernst Jan M Speel
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Véronique Winnepenninckx
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Axel Zur Hausen
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.
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33
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Suares A, Medina MV, Coso O. Autophagy in Viral Development and Progression of Cancer. Front Oncol 2021; 11:603224. [PMID: 33763351 PMCID: PMC7982729 DOI: 10.3389/fonc.2021.603224] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.
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Affiliation(s)
- Alejandra Suares
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Victoria Medina
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Omar Coso
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
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34
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Suares A, Medina MV, Coso O. Autophagy in Viral Development and Progression of Cancer. Front Oncol 2021. [DOI: 10.3389/fonc.2021.603224
expr 816899697 + 824303767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.
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35
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Mokánszki A, Méhes G, Csoma SL, Kollár S, Chang Chien YC. Molecular Profiling of Merkel Cell Polyomavirus-Associated Merkel Cell Carcinoma and Cutaneous Melanoma. Diagnostics (Basel) 2021; 11:diagnostics11020212. [PMID: 33535453 PMCID: PMC7912722 DOI: 10.3390/diagnostics11020212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
Merkel cell carcinoma (MCC) is a rare, high-grade, aggressive cutaneous neuroendocrine malignancy most commonly associated with sun-exposed areas of older individuals. A relatively newly identified human virus, the Merkel cell polyomavirus (MCPyV) has been implicated in the pathogenesis of MCC. Our study aimed to examine nine MCC cases and randomly selected 60 melanoma cases to identify MCPyV status and to elucidate genetic differences between virus-positive and -negative cases. Altogether, seven MCPyV-positive MCC samples and four melanoma samples were analyzed. In MCPyV-positive MCC RB1, TP53, FBXW7, CTNNB1, and HNF1A pathogenic variants were identified, while in virus-negative cases only benign variants were found. In MCPyV-positive melanoma cases, besides BRAF mutations the following genes were also affected: PIK3CA, STK11, CDKN2A, SMAD4, and APC. In contrast to studies found in the literature, a higher tumor burden was detected in virus-associated MCC compared to MCPyV-negative cases. No association was identified between virus infection and tumor burden in melanoma samples. We concluded that analyzing the key morphologic and immunohistological features of MCC is critical to avoid confusion with other cutaneous malignancies. Molecular genetic investigations such as next-generation sequencing (NGS) enable molecular stratification, which may have future clinical impact.
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Affiliation(s)
- Attila Mokánszki
- Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (G.M.); (S.L.C.); (Y.-C.C.C.)
- Correspondence: ; Tel.: +36-52-411-600
| | - Gábor Méhes
- Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (G.M.); (S.L.C.); (Y.-C.C.C.)
| | - Szilvia Lilla Csoma
- Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (G.M.); (S.L.C.); (Y.-C.C.C.)
| | - Sándor Kollár
- Department of Pathology, Kenézy Gyula Teaching Hospital, University of Debrecen, H-4032 Debrecen, Hungary;
| | - Yi-Che Chang Chien
- Department of Pathology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (G.M.); (S.L.C.); (Y.-C.C.C.)
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36
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Scott TA, Morris KV. Designer nucleases to treat malignant cancers driven by viral oncogenes. Virol J 2021; 18:18. [PMID: 33441159 PMCID: PMC7805041 DOI: 10.1186/s12985-021-01488-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/02/2021] [Indexed: 11/22/2022] Open
Abstract
Viral oncogenic transformation of healthy cells into a malignant state is a well-established phenomenon but took decades from the discovery of tumor-associated viruses to their accepted and established roles in oncogenesis. Viruses cause ~ 15% of know cancers and represents a significant global health burden. Beyond simply causing cellular transformation into a malignant form, a number of these cancers are augmented by a subset of viral factors that significantly enhance the tumor phenotype and, in some cases, are locked in a state of oncogenic addiction, and substantial research has elucidated the mechanisms in these cancers providing a rationale for targeted inactivation of the viral components as a treatment strategy. In many of these virus-associated cancers, the prognosis remains extremely poor, and novel drug approaches are urgently needed. Unlike non-specific small-molecule drug screens or the broad-acting toxic effects of chemo- and radiation therapy, the age of designer nucleases permits a rational approach to inactivating disease-causing targets, allowing for permanent inactivation of viral elements to inhibit tumorigenesis with growing evidence to support their efficacy in this role. Although many challenges remain for the clinical application of designer nucleases towards viral oncogenes; the uniqueness and clear molecular mechanism of these targets, combined with the distinct advantages of specific and permanent inactivation by nucleases, argues for their development as next-generation treatments for this aggressive group of cancers.
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Affiliation(s)
- Tristan A Scott
- Center for Gene Therapy, City of Hope, Beckman Research Institute and Hematological Malignancy and Stem Cell Transplantation Institute at the City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.
| | - Kevin V Morris
- Center for Gene Therapy, City of Hope, Beckman Research Institute and Hematological Malignancy and Stem Cell Transplantation Institute at the City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA
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37
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Spurgeon ME, Liem A, Buehler D, Cheng J, DeCaprio JA, Lambert PF. The Merkel Cell Polyomavirus T Antigens Function as Tumor Promoters in Murine Skin. Cancers (Basel) 2021; 13:cancers13020222. [PMID: 33435392 PMCID: PMC7827793 DOI: 10.3390/cancers13020222] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/05/2021] [Accepted: 01/08/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Merkel cell polyomavirus, a recently discovered human virus, is linked to the development of a rare form of skin cancer called Merkel cell carcinoma. The virus does not replicate in cancer cells, yet there is continued expression of viral proteins known as T antigens. The T antigens are believed to contribute to Merkel cell carcinoma development, yet how they do so remains an active area of research. In this study, we used transgenic mice expressing the viral T antigens in their skin to determine at which stage of skin cancer development these viral proteins function. We discovered that the Merkel cell polyomavirus T antigens function as tumor promoters, rather than tumor initiators, in the skin. These findings suggest that other tumor-initiating events may cooperate with the tumor-promoting activities of the viral T antigens, thus providing important insight into how Merkel cell polyomavirus can cause cancer in human skin. Abstract Merkel cell polyomavirus (MCPyV) causes the majority of human Merkel cell carcinomas (MCC), a rare but highly aggressive form of skin cancer. We recently reported that constitutive expression of MCC tumor-derived MCPyV tumor (T) antigens in the skin of transgenic mice leads to hyperplasia, increased proliferation, and spontaneous epithelial tumor development. We sought to evaluate how the MCPyV T antigens contribute to tumor formation in vivo using a classical, multi-stage model for squamous cell carcinoma development. In this model, two chemical carcinogens, DMBA and TPA, contribute to two distinct phases of carcinogenesis—initiation and promotion, respectively—that are required for tumors to develop. By treating the MCPyV transgenic mice with each chemical carcinogen, we determined how the viral oncogenes contributed to carcinogenesis. We observed that the MCPyV T antigens synergized with the tumor initiator DMBA, but not with the tumor promoter TPA, cause tumors. Therefore, the MCPyV tumor antigens function primarily as tumor promoters, similar to that seen with human papillomavirus (HPV) oncoproteins. These studies provide insight into the role of MCPyV T antigen expression in tumor formation in vivo and contribute to our understanding of how MCPyV may function as a human DNA tumor virus.
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Affiliation(s)
- Megan E. Spurgeon
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
- Correspondence: (M.E.S.); (P.F.L.)
| | - Amy Liem
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
| | - Darya Buehler
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
| | - Jingwei Cheng
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH 03824, USA;
| | - James A. DeCaprio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
- Correspondence: (M.E.S.); (P.F.L.)
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38
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Benisty D, Kay S, Rund D, Katz BZ. Differential diagnosis of malignant mononuclear cells in the cerebrospinal fluid: Merkel carcinoma cells. Diagn Cytopathol 2020; 49:443-445. [PMID: 33264487 DOI: 10.1002/dc.24664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 10/08/2020] [Accepted: 11/03/2020] [Indexed: 11/06/2022]
Affiliation(s)
- Dan Benisty
- Department of Hematology, Tel-Aviv University, Tel Aviv, Israel
| | - Sigi Kay
- Department of Hematology, Tel-Aviv University, Tel Aviv, Israel
| | - Deborah Rund
- Department of Hematology, Tel-Aviv University, Tel Aviv, Israel
| | - Ben-Zion Katz
- Department of Hematology, Tel-Aviv University, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
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39
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Toptan T, Cantrell PS, Zeng X, Liu Y, Sun M, Yates NA, Chang Y, Moore PS. Proteomic approach to discover human cancer viruses from formalin-fixed tissues. JCI Insight 2020; 5:143003. [PMID: 33055416 PMCID: PMC7710300 DOI: 10.1172/jci.insight.143003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/07/2020] [Indexed: 12/11/2022] Open
Abstract
The challenge of discovering a completely new human tumor virus of unknown phylogeny or sequence depends on detecting viral molecules and differentiating them from host molecules in the virus-associated neoplasm. We developed differential peptide subtraction (DPS) using differential mass spectrometry (dMS) followed by targeted analysis to facilitate this discovery. We validated this approach by analyzing Merkel cell carcinoma (MCC), an aggressive human neoplasm, in which ~80% of cases are caused by the human Merkel cell polyomavirus (MCV). Approximately 20% of MCC have a high mutational burden and are negative for MCV, but are microscopically indistinguishable from virus positive cases. Using 23 (12 MCV+, 11 MCV-) formalin-fixed MCC, DPS identified both viral and human biomarkers (MCV large T antigen, CDKN2AIP, SERPINB5, and TRIM29) that discriminate MCV+ and MCV- MCC. Statistical analysis of 498,131 dMS features not matching the human proteome by DPS revealed 562 (0.11%) to be upregulated in virus-infected samples. Remarkably, 4 (20%) of the top 20 candidate MS spectra originated from MCV T oncoprotein peptides and confirmed by reverse translation degenerate oligonucleotide sequencing. DPS is a robust proteomic approach to identify potentially novel viral sequences in infectious tumors when nucleic acid-based methods are not feasible.
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Affiliation(s)
- Tuna Toptan
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Institute of Medical Virology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
| | | | | | - Yang Liu
- Biomedical Mass Spectrometry Center and
| | - Mai Sun
- Biomedical Mass Spectrometry Center and
| | - Nathan A. Yates
- Biomedical Mass Spectrometry Center and
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yuan Chang
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Patrick S. Moore
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Hall ET, Fernandez-Lopez E, Silk AW, Dummer R, Bhatia S. Immunologic Characteristics of Nonmelanoma Skin Cancers: Implications for Immunotherapy. Am Soc Clin Oncol Educ Book 2020; 40:1-10. [PMID: 32207669 DOI: 10.1200/edbk_278953] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In this review, we summarize the immunology of nonmelanoma skin cancers (NMSCs) and the clinical data with immunotherapy in this heterogeneous group of cancers that include basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (CSCC), and Merkel cell carcinoma (MCC). NMSCs are exceedingly common, and their treatment consumes substantial health care resources. Annual global mortality from NMSCs is comparable to that from malignant melanoma. Although the majority of NMSCs are localized at diagnosis and are treated effectively with surgery, metastases (nodal and distant) can sometimes arise and require systemic therapy. Given the success of immunotherapy in treating cutaneous melanoma, there has been an increasing interest in studying the immunology of NMSCs. Immunocompromised patients have a substantially higher risk of developing NMSCs (particularly CSCC and MCC), suggesting a role of the immune system in the pathogenesis of these cancers. Similar to cutaneous melanoma, the pathogenesis of BCC, CSCC, and virus-negative MCC is related to DNA damage from ultraviolet radiation exposure, and these cancers have a very high tumor mutational burden, which likely results in higher levels of tumor neoantigens that may be targets for the immune system. Viral antigens in virus-positive MCC are also strongly immunogenic. Emerging data from clinical trials of immune checkpoint inhibitors in NMSCs look very promising and are rapidly changing the treatment landscape of these cancers. Specifically, pembrolizumab and avelumab are U.S. Food and Drug Administration-approved for treatment of metastatic MCC and cemiplimab for metastatic CSCC. Several ongoing trials are investigating novel immunotherapies (monotherapies as well as combination) for treatment of NMSCs.
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Affiliation(s)
- Evan T Hall
- Division of Medical Oncology, University of Washington, Seattle, WA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Ann W Silk
- Dana-Farber Cancer Institute, Boston, MA
| | - Reinhard Dummer
- Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland
| | - Shailender Bhatia
- Division of Medical Oncology, University of Washington, Seattle, WA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
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Abstract
PURPOSE OF REVIEW Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer, which is associated in 80% of cases with the Merkel cell polyomavirus (MCPyV). Advanced stages respond to immune checkpoint inhibitors in 50% of cases. Major issues remain unanswered regarding its oncogenesis and optimal treatment. RECENT FINDINGS MCPyV-negative and MCPyV-positive MCCs have been hypothesized to derive from distinct cells, although the cell of origin remains a matter of debate. The crucial role the MCPyV small T oncoprotein was recently confirmed by its ability to inactivate p53, together with its contribution to the metastatic progression. In advanced cases, tumoral microenvironment may adequately predict responses to immunotherapies, and several mechanisms of primary and secondary resistance have been investigated. SUMMARY Identifying the mechanisms of oncogenesis allow experimentation of new therapeutic targets, which remain mandatory even at the era of immunotherapies. Although new insights in the mechanisms of primary and secondary resistance pave the way for development of further immunotherapy strategies, neoadjuvant strategies may challenge our whole approach of the disease.
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Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth. Viruses 2020; 12:v12091043. [PMID: 32962090 PMCID: PMC7551350 DOI: 10.3390/v12091043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/14/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023] Open
Abstract
Merkel cell polyomavirus (MCV) is the only known human oncogenic virus in the polyomaviridae family and the etiological agent of most Merkel cell carcinomas (MCC). MCC is an aggressive and highly metastatic skin cancer with a propensity for recurrence and poor prognosis. Large tumor antigen (LT), is an essential oncoprotein for MCV transcription, viral replication, and cancer cell proliferation. MCV LT is a short-lived protein that encodes a unique domain: MCV LT unique regions (MURs). These domains consist of phosphorylation sites that interact with multiple E3 ligases, thus limiting LT expression and consequently, viral replication. In this study, we show that MURs are necessary for regulating LT stability via multiple E3 ligase interactions, resulting in cell growth arrest. While expression of wild-type MCV LT induced a decrease in cellular proliferation, deletion of the MUR domains resulted in increased LT stability and cell proliferation. Conversely, addition of MURs to SV40 LT propagated E3 ligase interactions, which in turn, reduced SV40 LT stability and decreased cell growth activity. Our results demonstrate that compared to other human polyomaviruses (HPyVs), MCV LT has evolved to acquire the MUR domains that are essential for MCV LT autoregulation, potentially leading to viral latency and MCC.
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Topalian SL, Bhatia S, Amin A, Kudchadkar RR, Sharfman WH, Lebbé C, Delord JP, Dunn LA, Shinohara MM, Kulikauskas R, Chung CH, Martens UM, Ferris RL, Stein JE, Engle EL, Devriese LA, Lao CD, Gu J, Li B, Chen T, Barrows A, Horvath A, Taube JM, Nghiem P. Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial. J Clin Oncol 2020; 38:2476-2487. [PMID: 32324435 PMCID: PMC7392746 DOI: 10.1200/jco.20.00201] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2020] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC. METHODS In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.
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Affiliation(s)
- Suzanne L. Topalian
- Johns Hopkins Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | | | - Asim Amin
- Levine Cancer Institute, Atrium Healthcare, Charlotte, NC
| | | | - William H. Sharfman
- Johns Hopkins Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Celeste Lebbé
- Université de Paris, INSERM U976, and Dermatology and CIC, AP-HP, Saint Louis Hospital, Paris, France
| | | | - Lara A. Dunn
- Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Rima Kulikauskas
- University of Washington, Seattle Cancer Care Alliance, Seattle, WA
| | | | | | - Robert L. Ferris
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA
| | - Julie E. Stein
- Johns Hopkins Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Elizabeth L. Engle
- Johns Hopkins Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Lot A. Devriese
- University Medical Center Utrecht, Cancer Center, Utrecht, the Netherlands
| | | | | | - Bin Li
- Bristol Myers Squibb, Princeton, NJ
| | | | | | | | - Janis M. Taube
- Johns Hopkins Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Paul Nghiem
- University of Washington, Seattle Cancer Care Alliance, Seattle, WA
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Czech-Sioli M, Günther T, Therre M, Spohn M, Indenbirken D, Theiss J, Riethdorf S, Qi M, Alawi M, Wülbeck C, Fernandez-Cuesta I, Esmek F, Becker JC, Grundhoff A, Fischer N. High-resolution analysis of Merkel Cell Polyomavirus in Merkel Cell Carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms. PLoS Pathog 2020; 16:e1008562. [PMID: 32833988 PMCID: PMC7470373 DOI: 10.1371/journal.ppat.1008562] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 09/03/2020] [Accepted: 07/08/2020] [Indexed: 12/17/2022] Open
Abstract
Merkel Cell Polyomavirus (MCPyV) is the etiological agent of the majority of Merkel Cell Carcinomas (MCC). MCPyV positive MCCs harbor integrated, defective viral genomes that constitutively express viral oncogenes. Which molecular mechanisms promote viral integration, if distinct integration patterns exist, and if integration occurs preferentially at loci with specific chromatin states is unknown. We here combined short and long-read (nanopore) next-generation sequencing and present the first high-resolution analysis of integration site structure in MCC cell lines as well as primary tumor material. We find two main types of integration site structure: Linear patterns with chromosomal breakpoints that map closely together, and complex integration loci that exhibit local amplification of genomic sequences flanking the viral DNA. Sequence analysis suggests that linear patterns are produced during viral replication by integration of defective/linear genomes into host DNA double strand breaks via non-homologous end joining, NHEJ. In contrast, our data strongly suggest that complex integration patterns are mediated by microhomology-mediated break-induced replication, MMBIR. Furthermore, we show by ChIP-Seq and RNA-Seq analysis that MCPyV preferably integrates in open chromatin and provide evidence that viral oncogene expression is driven by the viral promoter region, rather than transcription from juxtaposed host promoters. Taken together, our data explain the characteristics of MCPyV integration and may also provide a model for integration of other oncogenic DNA viruses such as papillomaviruses.
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Affiliation(s)
- Manja Czech-Sioli
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Günther
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Marlin Therre
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Spohn
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Daniela Indenbirken
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Juliane Theiss
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Sabine Riethdorf
- Institute of Tumorbiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Minyue Qi
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malik Alawi
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Corinna Wülbeck
- Translational skin cancer research, German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany
| | - Irene Fernandez-Cuesta
- Institute of Nanostructure- and Solid State Physics (INF), Center for Hybrid Nanostructures (CHyN), University of Hamburg, Hamburg, Germany
| | - Franziska Esmek
- Institute of Nanostructure- and Solid State Physics (INF), Center for Hybrid Nanostructures (CHyN), University of Hamburg, Hamburg, Germany
| | - Jürgen C. Becker
- Translational skin cancer research, German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany
- Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Adam Grundhoff
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- * E-mail: (AG); (NF)
| | - Nicole Fischer
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- * E-mail: (AG); (NF)
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Pietropaolo V, Prezioso C, Moens U. Merkel Cell Polyomavirus and Merkel Cell Carcinoma. Cancers (Basel) 2020; 12:E1774. [PMID: 32635198 PMCID: PMC7407210 DOI: 10.3390/cancers12071774] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/26/2020] [Accepted: 06/28/2020] [Indexed: 12/12/2022] Open
Abstract
Viruses are the cause of approximately 15% of all human cancers. Both RNA and DNA human tumor viruses have been identified, with Merkel cell polyomavirus being the most recent one to be linked to cancer. This virus is associated with about 80% of Merkel cell carcinomas, a rare, but aggressive cutaneous malignancy. Despite its name, the cells of origin of this tumor may not be Merkel cells. This review provides an update on the structure and life cycle, cell tropism and epidemiology of the virus and its oncogenic properties. Putative strategies to prevent viral infection or treat virus-positive Merkel cell carcinoma patients are discussed.
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Affiliation(s)
- Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy; (V.P.); (C.P.)
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy; (V.P.); (C.P.)
- IRCSS San Raffaele Pisana, Microbiology of Chronic Neuro-Degenerative Pathologies, 00166 Rome, Italy
| | - Ugo Moens
- Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø—The Arctic University of Norway, 9037 Tromsø, Norway
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Abstract
Viral infection underlies a significant share of the global cancer burden. Merkel cell polyomavirus (MCPyV) is the newest member of the human oncogenic virus family. Its discovery over a decade ago marked the beginning of an exciting era in human tumor virology. Since then, significant evidence has emerged to support the etiologic role of MCPyV in Merkel cell carcinoma (MCC), an extremely lethal form of skin cancer. MCPyV infection is widespread in the general population. MCC diagnoses have tripled over the past 20 years, but effective treatments are currently lacking. In this review, we highlight recent discoveries that have shaped our understanding of MCPyV oncogenic mechanism and host cellular tropism, as well as the molecular events occurring in the viral infectious life cycle. These insights will guide future efforts in developing novel virus-targeted therapeutic strategies for treating the devastating human cancers associated with this new tumorigenic virus.
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Affiliation(s)
- Wei Liu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6076, USA;
| | - Jianxin You
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6076, USA;
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An Algorithmic Immunohistochemical Approach to Define Tumor Type and Assign Site of Origin. Adv Anat Pathol 2020; 27:114-163. [PMID: 32205473 DOI: 10.1097/pap.0000000000000256] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Immunohistochemistry represents an indispensable complement to an epidemiology and morphology-driven approach to tumor diagnosis and site of origin assignment. This review reflects the state of my current practice, based on 15-years' experience in Pathology and a deep-dive into the literature, always striving to be better equipped to answer the age old questions, "What is it, and where is it from?" The tables and figures in this manuscript are the ones I "pull up on the computer" when I am teaching at the microscope and turn to myself when I am (frequently) stuck. This field is so exciting because I firmly believe that, through the application of next-generation immunohistochemistry, we can provide better answers than ever before. Specific topics covered in this review include (1) broad tumor classification and associated screening markers; (2) the role of cancer epidemiology in determining pretest probability; (3) broad-spectrum epithelial markers; (4) noncanonical expression of broad tumor class screening markers; (5) a morphologic pattern-based approach to poorly to undifferentiated malignant neoplasms; (6) a morphologic and immunohistochemical approach to define 4 main carcinoma types; (7) CK7/CK20 coordinate expression; (8) added value of semiquantitative immunohistochemical stain assessment; algorithmic immunohistochemical approaches to (9) "garden variety" adenocarcinomas presenting in the liver, (10) large polygonal cell adenocarcinomas, (11) the distinction of primary surface ovarian epithelial tumors with mucinous features from metastasis, (12) tumors presenting at alternative anatomic sites, (13) squamous cell carcinoma versus urothelial carcinoma, and neuroendocrine neoplasms, including (14) the distinction of pheochromocytoma/paraganglioma from well-differentiated neuroendocrine tumor, site of origin assignment in (15) well-differentiated neuroendocrine tumor and (16) poorly differentiated neuroendocrine carcinoma, and (17) the distinction of well-differentiated neuroendocrine tumor G3 from poorly differentiated neuroendocrine carcinoma; it concludes with (18) a discussion of diagnostic considerations in the broad-spectrum keratin/CD45/S-100-"triple-negative" neoplasm.
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Xia YJ, Cao DS, Zhao J, Zhu BZ, Xie J. Frequency and prognosis of metastasis to liver, lung, bone and brain from Merkel cell carcinoma. Future Oncol 2020; 16:1101-1113. [PMID: 32314598 DOI: 10.2217/fon-2020-0064] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Aim: To describe the factors affecting distant metastasis of Merkel cell carcinoma (MCC) and the prognosis of metastatic MCC. Materials & methods: The MCC patient information was downloaded from the SEER database. Logistic regression and Cox proportional hazard models were conducted to screen for significant factors. Results: A total of 3449 patients were enrolled. Surgery and chemotherapy were significantly correlated with the occurrence of distant metastasis. In the cause-specific survival rate of MCC, regional lymph node removal, sentinel lymph node biopsy, radiation and chemotherapy can significantly reduce the prognostic risk of patients with distant metastases. Conclusion: Our study screened out the factors affecting the distant metastasis and prognosis of MCC and more prospective studies are needed to verify our findings.
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Affiliation(s)
- Yi-Jun Xia
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui Province, PR China
| | - Dong-Sheng Cao
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui Province, PR China
| | - Jun Zhao
- Department of Dermatology, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui Province, PR China
| | - Bang-Zhong Zhu
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui Province, PR China
| | - Juan Xie
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui Province, PR China
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Abstract
This review serves as a primer on contemporary neuroendocrine neoplasm classification, with an emphasis on gastroenteropancreatic well-differentiated neuroendocrine tumors. Topics discussed include general features of neuroendocrine neoplasms, general neuroendocrine marker immunohistochemistry, the distinction of well-differentiated neuroendocrine tumor from pheochromocytoma/paraganglioma and other diagnostic mimics and poorly differentiated neuroendocrine carcinoma from diagnostic mimics, the concepts of differentiation and grade and the application of Ki-67 immunohistochemistry to determine the latter, the various WHO classifications of neuroendocrine neoplasms including the 2019 WHO classification of gastroenteropancreatic tumors, organ-specific considerations for gastroenteropancreatic well-differentiated neuroendocrine tumors, immunohistochemistry to determine site of origin in metastatic well-differentiated neuroendocrine tumor of occult origin, immunohistochemistry in the distinction of well-differentiated neuroendocrine tumor G3 from large cell neuroendocrine carcinoma, and, finally, required and recommended reporting elements for biopsies and resections of gastroenteropancreatic neuroendocrine epithelial neoplasms.
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Affiliation(s)
- Andrew M Bellizzi
- Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.
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50
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Starrett GJ, Thakuria M, Chen T, Marcelus C, Cheng J, Nomburg J, Thorner AR, Slevin MK, Powers W, Burns RT, Perry C, Piris A, Kuo FC, Rabinowits G, Giobbie-Hurder A, MacConaill LE, DeCaprio JA. Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma. Genome Med 2020; 12:30. [PMID: 32188490 PMCID: PMC7081548 DOI: 10.1186/s13073-020-00727-4] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 02/27/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet-induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. However, it has been challenging to reliably distinguish between virus positive and UV damaged MCC. METHODS In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a clinically implemented, next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome and software to detect integration sites and structure. RESULTS Sequencing from this approach revealed distinct integration junctions in the tumor genome and generated assemblies that strongly support a model of microhomology-initiated hybrid, virus-host, circular DNA intermediate that promotes focal amplification of host and viral DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Finally, comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival. CONCLUSIONS These results demonstrate the value of high-confidence virus detection for identifying molecular mechanisms of UV and viral oncogenesis in MCC. Furthermore, integrating these data with clinical data revealed features that could impact patient outcome and improve our understanding of MCC risk factors.
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Affiliation(s)
| | - Manisha Thakuria
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Merkel Cell Carcinoma Center of Excellence, Dana-Farber/Brigham Cancer Center, Boston, MA, USA
| | - Tianqi Chen
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Christina Marcelus
- Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer 440, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Jingwei Cheng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer 440, 450 Brookline Avenue, Boston, MA, 02215, USA
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jason Nomburg
- Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer 440, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Aaron R Thorner
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Michael K Slevin
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Winslow Powers
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Robert T Burns
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Caitlin Perry
- Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Adriano Piris
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Frank C Kuo
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Guilherme Rabinowits
- Merkel Cell Carcinoma Center of Excellence, Dana-Farber/Brigham Cancer Center, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer 440, 450 Brookline Avenue, Boston, MA, 02215, USA
- Present Address: Miami Cancer Institute, Miami, FL, USA
| | | | - Laura E MacConaill
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - James A DeCaprio
- Merkel Cell Carcinoma Center of Excellence, Dana-Farber/Brigham Cancer Center, Boston, MA, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer 440, 450 Brookline Avenue, Boston, MA, 02215, USA.
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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