Skip to main content

Merkel Cell Polyomavirus: A New DNA Virus Associated with Human Cancer

  • Chapter
  • First Online:
Infectious Agents Associated Cancers: Epidemiology and Molecular Biology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1018))

Abstract

Merkel cell polyomavirus (MCPyV or MCV) is a novel human polyomavirus that has been discovered in Merkel cell carcinoma (MCC), a highly aggressive skin cancer. MCPyV infection is widespread in the general population. MCPyV-associated MCC is one of the most aggressive skin cancers, killing more patients than other well-known cancers such as cutaneous T-cell lymphoma and chronic myelogenous leukemia (CML). Currently, however, there is no effective drug for curing this cancer. The incidence of MCC has tripled over the past two decades. With the widespread infection of MCPyV and the increase in MCC diagnoses, it is critical to better understand the biology of MCPyV and its oncogenic potential. In this chapter, we summarize recent discoveries regarding MCPyV molecular virology, host cellular tropism, mechanisms of MCPyV oncoprotein-mediated oncogenesis, and current therapeutic strategies for MCPyV-associated MCC. We also present epidemiological evidence for MCPyV infection in HIV patients and links between MCPyV and non-MCC human cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Feng H, Shuda M, Chang Y, Moore PS (2008) Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Feng H, Taylor JL, Benos PV, Newton R, Waddell K, Lucas SB, Chang Y, Moore PS (2007) Human transcriptome subtraction by using short sequence tags to search for tumor viruses in conjunctival carcinoma. J Virol 81:11332–11340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang TS, Byrne PJ, Jacobs LK, Taube JM (2011) Merkel cell carcinoma: update and review. Semin Cutan Med Surg 30:48–56

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Lemos BD, Storer BE, Iyer JG, Phillips JL, Bichakjian CK, Fang LC, Johnson TM, Liegeois-Kwon NJ, Otley CC, Paulson KG, Ross MI, Yu SS, Zeitouni NC, Byrd DR, Sondak VK, Gershenwald JE, Sober AJ, Nghiem P (2010) Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 63:751–761

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chang Y, Moore PS (2012) Merkel cell carcinoma: a virus-induced human cancer. Annu Rev Pathol 7:123–144

    Article  CAS  PubMed  Google Scholar 

  6. Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang LC, Peñas PF, Nghiem P (2008) Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 58:375–381

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sastre-Garau X, Peter M, Avril MF, Laude H, Couturier J, Rozenberg F, Almeida A, Boitier F, Carlotti A, Couturaud B, Dupin N (2009) Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J Pathol 218:48–56

    Article  CAS  PubMed  Google Scholar 

  8. Houben R, Shuda M, Weinkam R, Schrama D, Feng H, Chang Y, Moore PS, Becker JC (2010) Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. J Virol 84:7064–7072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kean JM, Rao S, Wang M, Garcea RL (2009) Seroepidemiology of human polyomaviruses. PLoS Pathog 5:e1000363

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Pastrana DV, Tolstov YL, Becker JC, Moore PS, Chang Y, Buck CB (2009) Quantitation of human seroresponsiveness to Merkel cell polyomavirus. PLoS Pathog 5:e1000578

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ, Moschos S, Chang Y, Buck CB, Moore PS (2009) Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer 125:1250–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gjoerup O, Chang Y (2010) Chapter 1 – update on human polyomaviruses and cancer. In: George FVW, George K (eds) Adv Cancer Res, vol. Volume 106. Academic Press, Cambridge, MA, pp 1–51

    Google Scholar 

  13. Liu W, MacDonald M, You J (2016) Merkel cell polyomavirus infection and Merkel cell carcinoma. Curr Opin Virol 20:20–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shuda M, Feng H, Kwun HJ, Rosen ST, Gjoerup O, Moore PS, Chang Y (2008) T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A 105:16272–16277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kwun HJ, Guastafierro A, Shuda M, Meinke G, Bohm A, Moore PS, Chang Y (2009) The minimum replication origin of Merkel cell polyomavirus has a unique large T-antigen loading architecture and requires small T-antigen expression for optimal replication. J Virol 83:12118–12128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Diaz J, Wang X, Tsang SH, Jiao J, You J (2014) Phosphorylation of large T antigen regulates merkel cell polyomavirus replication. Cancers (Basel) 6:1464–1486

    Article  CAS  Google Scholar 

  17. Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB, Brautigan DL, Roberts TM (1990) Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 60:167–176

    Article  CAS  PubMed  Google Scholar 

  18. Shuda M, Kwun HJ, Feng H, Chang Y, Moore PS (2011) Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J Clin Invest 121:3623–3634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kwun HJ, Shuda M, Feng H, Camacho CJ, Moore PS, Chang Y (2013) Merkel cell polyomavirus small T antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCFFbw7. Cell Host Microbe 14:125–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsang SH, Wang R, Nakamaru-Ogiso E, Knight SA, Buck CB, You J (2016) The oncogenic small tumor antigen of Merkel cell polyomavirus is an iron-sulfur cluster protein that enhances viral DNA replication. J Virol 90:1544–1556

    Article  CAS  PubMed Central  Google Scholar 

  21. Carter JJ, Daugherty MD, Qi X, Bheda-Malge A, Wipf GC, Robinson K, Roman A, Malik HS, Galloway DA (2013) Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes. Proc Natl Acad Sci U S A 110:12744–12749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Spurgeon ME, Lambert PF (2013) Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology 435:118–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Feng H, Kwun HJ, Liu X, Gjoerup O, Stolz DB, Chang Y, Moore PS (2011) Cellular and viral factors regulating Merkel cell polyomavirus replication. PLoS One 6:e22468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Neumann F, Borchert S, Schmidt C, Reimer R, Hohenberg H, Fischer N, Grundhoff A (2011) Replication, gene expression and particle production by a consensus Merkel cell polyomavirus (MCPyV) genome. PLoS One 6:e29112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schowalter RM, Buck CB (2013) The Merkel cell polyomavirus minor capsid protein. PLoS Pathog 9:e1003558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schowalter RM, Pastrana DV, Buck CB (2011) Glycosaminoglycans and sialylated glycans sequentially facilitate Merkel cell polyomavirus infectious entry. PLoS Pathog 7:e1002161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Seo GJ, Chen CJ, Sullivan CS (2009) Merkel cell polyomavirus encodes a microRNA with the ability to autoregulate viral gene expression. Virology 383:183–187

    Article  CAS  PubMed  Google Scholar 

  28. Theiss JM, Gunther T, Alawi M, Neumann F, Tessmer U, Fischer N, Grundhoff A (2015) A comprehensive analysis of replicating Merkel cell polyomavirus genomes delineates the viral transcription program and suggests a role for mcv-miR-M1 in episomal persistence. PLoS Pathog 11:e1004974

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Doorbar J (2006) Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond) 110:525–541

    Article  CAS  Google Scholar 

  30. Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, Stanley MA (2012) The biology and life-cycle of human papillomaviruses. Vaccine 30(Suppl 5):F55–F70

    Article  CAS  PubMed  Google Scholar 

  31. Shuda M, Chang Y, Moore PS (2014) Merkel cell polyomavirus-positive Merkel cell carcinoma requires viral small T-antigen for cell proliferation. J Invest Dermatol 134:1479–1481

    Article  CAS  PubMed  Google Scholar 

  32. Houben R, Adam C, Baeurle A, Hesbacher S, Grimm J, Angermeyer S, Henzel K, Hauser S, Elling R, Brocker EB, Gaubatz S, Becker JC, Schrama D (2012) An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells. Int J Cancer 130:847–856

    Article  CAS  PubMed  Google Scholar 

  33. Li J, Wang X, Diaz J, Tsang SH, Buck CB, You J (2013) Merkel cell polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation. J Virol 87:9173–9188. PMCID: PMC3754048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cheng J, Rozenblatt-Rosen O, Paulson KG, Nghiem P, DeCaprio JA (2013) Merkel cell polyomavirus large T antigen has growth-promoting and inhibitory activities. J Virol 87:6118–6126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Verhaegen ME, Mangelberger D, Harms PW, Vozheiko TD, Weick JW, Wilbert DM, Saunders TL, Ermilov AN, Bichakjian CK, Johnson TM, Imperiale MJ, Dlugosz AA (2014) Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice. J Invest Dermatol 88:3144–3160

    Google Scholar 

  36. Goh G, Walradt T, Markarov V, Blom A, Riaz N, Doumani R, Stafstrom K, Moshiri A, Yelistratova L, Levinsohn J, Chan TA, Nghiem P, Lifton RP, Choi J (2016) Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 7:3403–3415

    Article  PubMed  Google Scholar 

  37. Wong SQ, Waldeck K, Vergara IA, Schroder J, Madore J, Wilmott JS, Colebatch AJ, De Paoli-Iseppi R, Li J, Lupat R, Semple T, Arnau GM, Fellowes A, Leonard JH, Hruby G, Mann GJ, Thompson JF, Cullinane C, Johnston M, Shackleton M, Sandhu S, Bowtell DD, Johnstone RW, Fox SB, McArthur GA, Papenfuss AT, Scolyer RA, Gill AJ, Hicks RJ, Tothill RW (2015) UV-associated mutations underlie the etiology of MCV-negative Merkel cell carcinomas. Cancer Res 75:5228–5234

    Article  CAS  PubMed  Google Scholar 

  38. Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu YM, Dhanasekaran SM, Palanisamy N, Siddiqui J, Cao X, Su F, Wang R, Xiao H, Kunju LP, Mehra R, Tomlins SA, Fullen DR, Bichakjian CK, Johnson TM, Dlugosz AA, Chinnaiyan AM (2015) The distinctive mutational spectra of polyomavirus-negative Merkel cell carcinoma. Cancer Res 75:3720–3727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Moshiri AS, Doumani R, Yelistratova L, Blom A, Lachance K, Shinohara MM, Delaney M, Chang O, McArdle S, Thomas H, Asgari MM, Huang ML, Schwartz SM, Nghiem P (2016) Polyomavirus-negative Merkel cell carcinoma: a more aggressive subtype based on analysis of 282 cases using multimodal tumor virus detection. J Invest Dermatol 136:2128–2130

    Article  CAS  Google Scholar 

  40. Barth H, Solis M, Kack-Kack W, Soulier E, Velay A, Fafi-Kremer S (2016) In vitro and in vivo models for the study of human polyomavirus infection. Virus 8:292

    Article  Google Scholar 

  41. Neu U, Hengel H, Blaum BS, Schowalter RM, Macejak D, Gilbert M, Wakarchuk WW, Imamura A, Ando H, Kiso M, Arnberg N, Garcea RL, Peters T, Buck CB, Stehle T (2012) Structures of Merkel cell polyomavirus VP1 complexes define a sialic acid binding site required for infection. PLoS Pathog 8:e1002738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schafer G, Blumenthal MJ, Katz AA (2015) Interaction of human tumor viruses with host cell surface receptors and cell entry. Virus 7:2592–2617

    Article  CAS  Google Scholar 

  43. Bhattacharjee S, Chattaraj S (2017) Entry, infection, replication, and egress of human polyomaviruses: an update. Can J Microbiol 63:193–211

    Article  CAS  PubMed  Google Scholar 

  44. Erickson KD, Garcea RL, Tsai B (2009) Ganglioside GT1b is a putative host cell receptor for the Merkel cell polyomavirus. J Virol 83:10275–10279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schowalter RM, Reinhold WC, Buck CB (2012) Entry tropism of BK and Merkel cell polyomaviruses in cell culture. PLoS One 7:e42181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Foulongne V, Sauvage V, Hebert C, Dereure O, Cheval J, Gouilh MA, Pariente K, Segondy M, Burguière A, Manuguerra J-C, Caro V, Eloit M (2012) Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing. PLoS One 7:e38499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB (2010) Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 7:509–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang X, Li J, Schowalter RM, Jiao J, Buck CB, You J (2012) Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication. PLoS Pathog 8:e1003021. PMCID:PMC3493480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu W, Yang R, Payne AS, Schowalter RM, Spurgeon ME, Lambert PF, Xu X, Buck CB, You J (2016) Identifying the target cells and mechanisms of Merkel cell polyomavirus infection. Cell Host Microbe 19:775–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–870

    CAS  PubMed  Google Scholar 

  51. Chen D, Jarrell A, Guo C, Lang R, Atit R (2012) Dermal beta-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation. Development 139:1522–1533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Peretti A, Borgogna C, Rossi D, De Paoli L, Bawadekar M, Zavattaro E, Boldorini R, De Andrea M, Gaidano G, Gariglio M (2014) Analysis of human beta-papillomavirus and Merkel cell polyomavirus infection in skin lesions and eyebrow hair bulbs from a cohort of patients with chronic lymphocytic leukaemia. Br J Dermatol 171:1525–1528

    Article  CAS  PubMed  Google Scholar 

  53. Cho S, Shin MH, Kim YK, Seo JE, Lee YM, Park CH, Chung JH (2009) Effects of infrared radiation and heat on human skin aging in vivo. J Investig Dermatol Symp Proc 14:15–19

    Article  CAS  PubMed  Google Scholar 

  54. Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, Voorhees JJ (1996) Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 379:335–339

    Article  CAS  PubMed  Google Scholar 

  55. Gill SE, Parks WC (2008) Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol 40:1334–1347

    Article  CAS  PubMed  Google Scholar 

  56. Quan T, Fisher GJ (2015) Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: a mini-review. Gerontology 61:427–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Quan T, Qin Z, Xia W, Shao Y, Voorhees JJ, Fisher GJ (2009) Matrix-degrading metalloproteinases in photoaging. J Investig Dermatol Symp Proc 14:20–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Varani J, Dame MK, Rittie L, Fligiel SE, Kang S, Fisher GJ, Voorhees JJ (2006) Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol 168:1861–1868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tilling T, Moll I (2012) Which are the cells of origin in merkel cell carcinoma? J Skin Cancer 2012:680410

    Article  PubMed  PubMed Central  Google Scholar 

  60. Moll I, Zieger W, Schmelz M (1996) Proliferative Merkel cells were not detected in human skin. Arch Dermatol Res 288:184–187

    Article  CAS  PubMed  Google Scholar 

  61. Vaigot P, Pisani A, Darmon YM, Ortonne JP (1987) The majority of epidermal Merkel cells are non-proliferative: a quantitative immunofluorescence analysis. Acta Derm Venereol 67:517–520

    CAS  PubMed  Google Scholar 

  62. Calder KB, Smoller BR (2010) New insights into merkel cell carcinoma. Adv Anat Pathol 17:155–161

    Article  PubMed  Google Scholar 

  63. Morrison KM, Miesegaes GR, Lumpkin EA, Maricich SM (2009) Mammalian Merkel cells are descended from the epidermal lineage. Dev Biol 336:76–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Van Keymeulen A, Mascre G, Youseff KK, Harel I, Michaux C, De Geest N, Szpalski C, Achouri Y, Bloch W, Hassan BA, Blanpain C (2009) Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. J Cell Biol 187:91–100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Zur Hausen A, Rennspiess D, Winnepenninckx V, Speel EJ, Kurz AK (2013) Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry. Cancer Res 73:4982–4987

    Article  CAS  PubMed  Google Scholar 

  66. Brummer GC, Bowen AR, Bowen GM (2016) Merkel cell carcinoma: current issues regarding diagnosis, management, and emerging treatment strategies. Am J Clin Dermatol 17:49–62

    Article  PubMed  Google Scholar 

  67. Rush Z, Fields RC, Lee N, Brownell I (2011) Radiation therapy in the management of Merkel cell carcinoma: current perspectives. Expert Rev Dermatol 6:395–404

    Article  PubMed  PubMed Central  Google Scholar 

  68. Saini AT, Miles BA (2015) Merkel cell carcinoma of the head and neck: pathogenesis, current and emerging treatment options. Onco Targets Ther 8:2157–2167

    PubMed  PubMed Central  Google Scholar 

  69. Cassler NM, Merrill D, Bichakjian CK, Brownell I (2016) Merkel cell carcinoma therapeutic update. Curr Treat Options in Oncol 17:36

    Article  Google Scholar 

  70. Paulson KG, Iyer JG, Tegeder AR, Thibodeau R, Schelter J, Koba S, Schrama D, Simonson WT, Lemos BD, Byrd DR, Koelle DM, Galloway DA, Leonard JH, Madeleine MM, Argenyi ZB, Disis ML, Becker JC, Cleary MA, Nghiem P (2011) Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 29:1539–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Inoue T, Yoneda K, Manabe M, Demitsu T (2000) Spontaneous regression of merkel cell carcinoma: a comparative study of TUNEL index and tumor-infiltrating lymphocytes between spontaneous regression and non-regression group. J Dermatol Sci 24:203–211

    Article  CAS  PubMed  Google Scholar 

  72. Paulson KG, Iyer JG, Blom A, Warton EM, Sokil M, Yelistratova L, Schuman L, Nagase K, Bhatia S, Asgari MM, Nghiem P (2013) Systemic immune suppression predicts diminished Merkel cell carcinoma-specific survival independent of stage. J Invest Dermatol 133:642–646

    Article  CAS  PubMed  Google Scholar 

  73. Aldabagh B, Joo J, Yu SS (2014) Merkel cell carcinoma: current status of targeted and future potential for immunotherapies. Semin Cutan Med Surg 33:76–82

    Article  PubMed  Google Scholar 

  74. Sihto H, Bohling T, Kavola H, Koljonen V, Salmi M, Jalkanen S, Joensuu H (2012) Tumor infiltrating immune cells and outcome of Merkel cell carcinoma: a population-based study. Clin Cancer Res 18:2872–2881

    Article  CAS  PubMed  Google Scholar 

  75. Schadendorf D, Lebbe C, Zur Hausen A, Avril MF, Hariharan S, Bharmal M, Becker JC (2017) Merkel cell carcinoma: epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer 71:53–69

    Article  PubMed  Google Scholar 

  76. Afanasiev OK, Yelistratova L, Miller N, Nagase K, Paulson K, Iyer JG, Ibrani D, Koelle DM, Nghiem P (2013) Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res 19:5351–5360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry S, Chartash EK, Daud A, Fling SP, Friedlander PA, Kluger HM, Kohrt HE, Lundgren L, Margolin K, Mitchell A, Olencki T, Pardoll DM, Reddy SA, Shantha EM, Sharfman WH, Sharon E, Shemanski LR, Shinohara MM, Sunshine JC, Taube JM, Thompson JA, Townson SM, Yearley JH, Topalian SL, Cheever MA (2016) PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 374:2542–2552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704

    Article  CAS  PubMed  Google Scholar 

  79. Mantripragada K, Birnbaum A (2015) Response to anti-PD-1 therapy in metastatic Merkel cell carcinoma metastatic to the heart and pancreas. Cureus 7:e403

    PubMed  PubMed Central  Google Scholar 

  80. Zeng Q, Gomez BP, Viscidi RP, Peng S, He L, Ma B, Wu TC, Hung CF (2012) Development of a DNA vaccine targeting Merkel cell polyomavirus. Vaccine 30:1322–1329

    Article  CAS  PubMed  Google Scholar 

  81. Gomez BP, Wang C, Viscidi RP, Peng S, He L, Wu TC, Hung CF (2012) Strategy for eliciting antigen-specific CD8+ T cell-mediated immune response against a cryptic CTL epitope of merkel cell polyomavirus large T antigen. Cell Biosci 2:36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wendzicki JA, Moore PS, Chang Y (2015) Large T and small T antigens of Merkel cell polyomavirus. Curr Opin Virol 11:38–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gomez B, He L, Tsai YC, Wu TC, Viscidi RP, Hung CF (2013) Creation of a Merkel cell polyomavirus small T antigen-expressing murine tumor model and a DNA vaccine targeting small T antigen. Cell Biosci 3:29

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Ma JE, Brewer JD (2014) Merkel cell carcinoma in immunosuppressed patients. Cancers (Basel) 6:1328–1350

    Article  Google Scholar 

  85. Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW (2002) Merkel cell carcinoma and HIV infection. Lancet 359:497–498

    Article  PubMed  Google Scholar 

  86. Wieland U, Silling S, Scola N, Potthoff A, Gambichler T, Brockmeyer NH, Pfister H, Kreuter A (2011) Merkel cell polyomavirus infection in HIV-positive men. Arch Dermatol 147:401–406

    Article  PubMed  Google Scholar 

  87. Kolia-Diafouka P, Foulongne V, Boulle N, Ngou J, Kelly H, Sawadogo B, Delany-Moretlwe S, Mayaud P, Segondy M, Group HS (2016) Detection of four human polyomaviruses (MCPyV, HPyV6, HPyV7 and TSPyV) in cervical specimens from HIV-infected and HIV-uninfected women. Sex Transm Infect 88:695–702

    Google Scholar 

  88. Vahabpour R, Nasimi M, Naderi N, Salehi-Vaziri M, Mohajel N, Sadeghi F, Keyvani H, Monavari SH (2017) Merkel cell polyomavirus IgG antibody levels are associated with progression to AIDS among HIV-infected individuals. Arch Virol 162:963–969

    Article  CAS  PubMed  Google Scholar 

  89. Fukumoto H, Sato Y, Hasegawa H, Katano H (2013) Frequent detection of Merkel cell polyomavirus DNA in sera of HIV-1-positive patients. Virol J 10:84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Li M, Saghafi N, Freymiller E, Basile JR, Lin YL (2013) Metastatic Merkel cell carcinoma of the oral cavity in a human immunodeficiency virus-positive patient and the detection of Merkel cell polyomavirus. Oral Surg Oral Med Oral Pathol Oral Radiol 115:e66–e71

    Article  PubMed  Google Scholar 

  91. Wieland U, Kreuter A (2011) Merkel cell polyomavirus infection and Merkel cell carcinoma in HIV-positive individuals. Curr Opin Oncol 23:488–493

    Article  PubMed  Google Scholar 

  92. Hourdequin KC, Lefferts JA, Brennick JB, Ernstoff MS, Tsongalis GJ, Pipas JM (2013) Merkel cell polyomavirus and extrapulmonary small cell carcinoma. Oncol Lett 6:1049–1052

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kim GJ, Lee JH, Lee DH (2017) Clinical and prognostic significance of Merkel cell polyomavirus in nonsmall cell lung cancer. Medicine (Baltimore) 96:e5413

    Article  Google Scholar 

  94. Hashida Y, Imajoh M, Nemoto Y, Kamioka M, Taniguchi A, Taguchi T, Kume M, Orihashi K, Daibata M (2013) Detection of Merkel cell polyomavirus with a tumour-specific signature in non-small cell lung cancer. Br J Cancer 108:629–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gheit T, Munoz JP, Levican J, Gonzalez C, Ampuero S, Parra B, Gaggero A, Corvalan AH, Meneses M, Tommasino M, Aguayo F (2012) Merkel cell polyomavirus in non-small cell lung carcinomas from Chile. Exp Mol Pathol 93:162–166

    Article  CAS  PubMed  Google Scholar 

  96. Colombara DV, Manhart LE, Carter JJ, Hawes SE, Weiss NS, Hughes JP, Qiao YL, Taylor PR, Smith JS, Galloway DA (2016) Absence of an association of human polyomavirus and papillomavirus infection with lung cancer in China: a nested case-control study. BMC Cancer 16:342

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Malhotra J, Waterboer T, Pawlita M, Michel A, Cai Q, Zheng W, Gao YT, Lan Q, Rothman N, Langseth H, Grimsrud TK, Yuan JM, Koh WP, Wang R, Arslan AA, Zeleniuch-Jacquotte A, Boffetta P (2016) Serum biomarkers of polyomavirus infection and risk of lung cancer in never smokers. Br J Cancer 115:1131–1139

    Article  CAS  PubMed  Google Scholar 

  98. Dworkin AM, Tseng SY, Allain DC, Iwenofu OH, Peters SB, Toland AE (2009) Merkel cell polyomavirus in cutaneous squamous cell carcinoma of immunocompetent individuals. J Invest Dermatol 129:2868–2874

    Article  CAS  PubMed  Google Scholar 

  99. Murakami M, Imajoh M, Ikawa T, Nakajima H, Kamioka M, Nemoto Y, Ujihara T, Uchiyama J, Matsuzaki S, Sano S, Daibata M (2011) Presence of Merkel cell polyomavirus in Japanese cutaneous squamous cell carcinoma. J Clin Virol 50:37–41

    Article  CAS  PubMed  Google Scholar 

  100. Kaibuchi-Noda K, Yokota K, Matsumoto T, Sawada M, Sakakibara A, Kono M, Tomita Y, Watanabe D, Fukumoto H, Katano H, Akiyama M (2011) Detection of Merkel cell polyomavirus in cutaneous squamous cell carcinoma before occurrence of Merkel cell carcinoma. J Am Acad Dermatol 65:e152–e154

    Article  PubMed  Google Scholar 

  101. Mertz KD, Paasinen A, Arnold A, Baumann M, Offner F, Willi N, Cathomas G (2013) Merkel cell polyomavirus large T antigen is detected in rare cases of nonmelanoma skin cancer. J Cutan Pathol 40:543–549

    Article  PubMed  Google Scholar 

  102. Reisinger DM, Shiffer JD, Cognetta AB Jr, Chang Y, Moore PS (2010) Lack of evidence for basal or squamous cell carcinoma infection with Merkel cell polyomavirus in immunocompetent patients with Merkel cell carcinoma. J Am Acad Dermatol 63:400–403

    Article  PubMed  Google Scholar 

  103. Mitteldorf C, Mertz KD, Fernandez-Figueras MT, Schmid M, Tronnier M, Kempf W (2012) Detection of Merkel cell polyomavirus and human papillomaviruses in Merkel cell carcinoma combined with squamous cell carcinoma in immunocompetent European patients. Am J Dermatopathol 34:506–510

    Article  PubMed  Google Scholar 

  104. Yahyapour Y, Sadeghi F, Alizadeh A, Rajabnia R, Siadati S (2016) Detection of Merkel cell polyomavirus and human papillomavirus in esophageal squamous cell carcinomas and non-cancerous esophageal samples in northern Iran. Pathol Oncol Res 22:667–672

    Article  CAS  PubMed  Google Scholar 

  105. Imajoh M, Hashida Y, Nemoto Y, Oguri H, Maeda N, Furihata M, Fukaya T, Daibata M (2012) Detection of Merkel cell polyomavirus in cervical squamous cell carcinomas and adenocarcinomas from Japanese patients. Virol J 9:154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Du-Thanh A, Dereure O, Guillot B, Foulongne V (2014) Merkel cell polyomavirus: its putative involvement in a particular subset of cutaneous lymphoma with possibly unfavorable outcome. J Clin Virol 61:161–165

    Article  CAS  PubMed  Google Scholar 

  107. Song Y, Gyarmati P (2017) Identification of Merkel cell polyomavirus from a patient with acute myeloid leukemia. Genome Announc 5:e01241-16

    Google Scholar 

  108. Cimino PJ Jr, Bahler DW, Duncavage EJ (2013) Detection of Merkel cell polyomavirus in chronic lymphocytic leukemia T-cells. Exp Mol Pathol 94:40–44

    Article  CAS  PubMed  Google Scholar 

  109. Pantulu ND, Pallasch CP, Kurz AK, Kassem A, Frenzel L, Sodenkamp S, Kvasnicka HM, Wendtner CM, Zur HA (2010) Detection of a novel truncating Merkel cell polyomavirus large T antigen deletion in chronic lymphocytic leukemia cells. Blood 116:5280–5284

    Article  CAS  PubMed  Google Scholar 

  110. Katano H, Ito H, Suzuki Y, Nakamura T, Sato Y, Tsuji T, Matsuo K, Nakagawa H, Sata T (2009) Detection of Merkel cell polyomavirus in Merkel cell carcinoma and Kaposi’s sarcoma. J Med Virol 81:1951–1958

    Article  CAS  PubMed  Google Scholar 

  111. Du-Thanh A, Guillot B, Dereure O, Foulongne V (2015) Detection of Merkel cell and other human polyomavirus DNA in lesional and nonlesional skin from patients with Kaposi sarcoma. Br J Dermatol 173:1063–1065

    Article  CAS  PubMed  Google Scholar 

  112. Urso C, Pierucci F, Sollai M, Arvia R, Massi D, Zakrzewska K (2016) Detection of Merkel cell polyomavirus and human papillomavirus DNA in porocarcinoma. J Clin Virol 78:71–73

    Article  CAS  PubMed  Google Scholar 

  113. Mertz KD, Schmid M, Burger B, Itin P, Palmedo G, Scharer L, Kutzner H, Fernandez Figueras MT, Cribier B, Pfaltz M, Kempf W (2011) Detection of Merkel cell polyomavirus in epidermodysplasia-verruciformis-associated skin neoplasms. Dermatology 222:87–92

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the members of our laboratory for helpful discussion and Dr. Wei Liu for helping with figure preparation. This work was supported in part by the National Institutes of Health (NIH) Grants R01CA148768, R01CA142723, and R01CA187718. Margo MacDonald is a Vagelos scholar in the Molecular Life Sciences and is supported by a Vagelos MLS summer stipend.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jianxin You .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

MacDonald, M., You, J. (2017). Merkel Cell Polyomavirus: A New DNA Virus Associated with Human Cancer. In: Cai, Q., Yuan, Z., Lan, K. (eds) Infectious Agents Associated Cancers: Epidemiology and Molecular Biology. Advances in Experimental Medicine and Biology, vol 1018. Springer, Singapore. https://doi.org/10.1007/978-981-10-5765-6_4

Download citation

Publish with us

Policies and ethics