New Virus Associated With Merkel Cell Carcinoma Development

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Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine malignancy of the skin with an annual incidence in the United States of 0.34 and 0.17 per 100,000 men and women, respectively. MCC incidence increases with age, is higher among men and whites, and positively correlates with solar ultraviolet (UV) index, suggesting UV radiation exposure may play a role in the development of MCC. MCC incidence rates are also higher among severely immunosuppressed populations, including people who have undergone organ transplantation, have lymphoma, and are HIV-infected. Given the increased risk for MCC observed with immunosuppression and the established associations between viral infections and other cancers that occur more often in immunosuppressed populations, MCC was a prime cancer candidate for a viral cause. Subsequent investigation discovered a genome encompassing 5387 base pairs of a new polyomavirus, subsequently named the Merkel cell polyomavirus.

Correspondence: Dana E. Rollison, PhD, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33647. E-mail: dana.rollison@moffitt.org
  • 1.

    AgelliMCleggLX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol2003;49:832841.

  • 2.

    MillerRWRabkinCS. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev1999;8:153158.

    • Search Google Scholar
    • Export Citation
  • 3.

    PennIFirstMR. Merkel's cell carcinoma in organ recipients: report of 41 cases. Transplantation1999;68:17171721.

  • 4.

    HowardRADoresGMCurtisRE. Merkel cell carcinoma and multiple primary cancers. Cancer Epidemiol Biomarkers Prev2006;15:15451549.

  • 5.

    EngelsEAFrischMGoedertJJ. Merkel cell carcinoma and HIV infection. Lancet2002;359:497498.

  • 6.

    ChangYCesarmanEPessinMS. Identification of herpesvirus-like DNA sequences in AIDS--associated Kaposi's sarcoma. Science1994;266:18651869.

    • Search Google Scholar
    • Export Citation
  • 7.

    EngelsEA. Infectious agents as causes of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev2007;16:401404.

  • 8.

    EngelsEABiggarRJHallHI. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer2008;123:187194.

    • Search Google Scholar
    • Export Citation
  • 9.

    GillisonMLShahKV. Chapter 9: role of mucosal human papillomavirus in nongenital cancers. J Natl Cancer Inst Monogr2003;31:5765.

  • 10.

    FengHShudaMChangYMoorePS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science2008;319:10961100.

  • 11.

    ShahKV. SV40 and human cancer: a review of recent data. Int J Cancer2007;120:215223.

  • 12.

    EddyBEBormanGSBerkeleyWHYoungRD. Tumors induced in hamsters by injection of rhesus monkey kidney cell extracts. Proc Soc Exp Biol Med1961;107:191197.

    • Search Google Scholar
    • Export Citation
  • 13.

    PadgettBLWalkerDLZuRheinGM. Cultivation of papova--like virus from human brain with progressive multifocal leucoencephalopathy. Lancet1971;1:12571260.

    • Search Google Scholar
    • Export Citation
  • 14.

    GardnerSDFieldAMColemanDVHulmeB. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet1971;1:12531257.

    • Search Google Scholar
    • Export Citation
  • 15.

    KnowlesW. Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). In:AhsanN ed. Polyomaviruses and human diseases. New York: Springer Science+Business Media; 2006:1945.

    • Search Google Scholar
    • Export Citation
  • 16.

    MonacoMCJensenPN. Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection. J Virol1998;72:99189923.

    • Search Google Scholar
    • Export Citation
  • 17.

    Bofill-MasSGironesR. Excretion and transmission of JCV in human populations. J Neurovirol2001;7:345349.

  • 18.

    Bofill-MasSGironesR. Role of the environment in the transmission of JC virus. J Neurovirol2003;9(Suppl 1):5458.

  • 19.

    KhaliliKGordonJWhiteMK. The polyomavirus, JCV and its involvement in human disease. Adv Exp Med Biol2006;577:274287.

  • 20.

    BonvoisinCWeekersLXhignesseP. Polyomavirus in renal transplantation: a hot problem. Transplantation2008;85:S4248.

  • 21.

    ShahK. Polyomaviruses. In:FieldsBKnipeDHowleyP eds. Fields virology. Philadelphia: Lippincott-Raven; 1996:20272043.

  • 22.

    GanDDKhaliliK. Interaction between JCV large T-antigen and beta-catenin. Oncogene2004;23:483490.

  • 23.

    ReissKKhaliliKGiordanoATrojanekJ. JC virus large T-antigen and IGF-I signaling system merge to affect DNA repair and genomic integrity. J Cell Physiol2006;206:295300.

    • Search Google Scholar
    • Export Citation
  • 24.

    TrojanekJCroulSHoT. T-antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51. J Cell Physiol2006;206:3546.

    • Search Google Scholar
    • Export Citation
  • 25.

    RollisonDEUtaipatURyschkewitschC. Investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories. Int. J Cancer2005;113:769774.

    • Search Google Scholar
    • Export Citation
  • 26.

    RollisonDEEngelsEAHalseyNA. Prediagnostic circulating antibodies to JC and BK human polyomaviruses and risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev2006;15:543550.

    • Search Google Scholar
    • Export Citation
  • 27.

    RollisonDE. Epidemiologic studies of polyomaviruses and cancer. In:AhsanN ed. Polyomaviruses and human diseases. New York: Landes Bioscience; 2006:342356.

    • Search Google Scholar
    • Export Citation
  • 28.

    RollisonDEHelzlsouerKJLeeJH. Prospective study of JC virus seroreactivity and the development of colorectal cancers and adenomas. Cancer Epidemiol Biomarkers Prev2009;18:15151523.

    • Search Google Scholar
    • Export Citation
  • 29.

    AllanderTAndreassonKGuptaS. Identification of a third human polyomavirus. J Virol2007;81:41304136.

  • 30.

    GaynorAMNissenMDWhileyDM. Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog2007;3:e64.

    • Search Google Scholar
    • Export Citation
  • 31.

    GiraudGRamqvistTRagnarsson-OldingBDalianisT. DNA from BK virus and JC virus and from KI, WU, and MC polyomaviruses as well as from simian virus 40 is not detected in non-UV-light-associated primary malignant melanomas of mucous membranes. J Clin Microbiol2008;46:35953598.

    • Search Google Scholar
    • Export Citation
  • 32.

    AndresCBelloniBPuchtaU. Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. J Cutan Pathol2009; in press.

  • 33.

    BeckerJCHoubenRUgurelS. MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol2009;129:248250.

    • Search Google Scholar
    • Export Citation
  • 34.

    BhatiaKGoedertJJModaliR. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. Int J Cancer2010;126:22402246.

    • Search Google Scholar
    • Export Citation
  • 35.

    BusamKJJungbluthAARekthmanN. Merkel cell polyomavirus expression in Merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am J Surg Pathol2009;33:13781385.

    • Search Google Scholar
    • Export Citation
  • 36.

    CarterJJPaulsonKGWipfGC. Association of Merkel cell polyomavirus-specific antibodies with Merkel cell carcinoma. J Natl Cancer Inst2009;101:15101522.

    • Search Google Scholar
    • Export Citation
  • 37.

    DuncavageEJZehnbauerBAPfeiferJD. Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma. Mod Pathol2009;22:516521.

  • 38.

    FoulongneVKlugerNDereureO. Merkel cell polyomavirus and Merkel cell carcinoma, France. Emerg Infect Dis2008;14:14911493.

  • 39.

    GarneskiKMWarcolaAHFengQ. Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol2009;129:246248.

    • Search Google Scholar
    • Export Citation
  • 40.

    HelmboldPLahtzCEnkA. Frequent occurrence of RASSF1A promoter hypermethylation and Merkel cell polyomavirus in Merkel cell carcinoma. Mol Carcinog2009;48:903909.

    • Search Google Scholar
    • Export Citation
  • 41.

    HoubenRSchramaDBeckerJC. Molecular pathogenesis of Merkel cell carcinoma. Exp Dermatol2009;18:193198.

  • 42.

    KassemASchopflinADiazC. Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res2008;68:50095013.

    • Search Google Scholar
    • Export Citation
  • 43.

    KatanoHItoHSuzukiY. Detection of Merkel cell polyomavirus in Merkel cell carcinoma and Kaposi's sarcoma. J Med Virol2009;81:19511958.

    • Search Google Scholar
    • Export Citation
  • 44.

    KoljonenVKukkoHPukkalaE. Chronic lymphocytic leukaemia patients have a high risk of Merkel-cell polyomavirus DNA-positive Merkel-cell carcinoma. Br J Cancer2009;101:14441447.

    • Search Google Scholar
    • Export Citation
  • 45.

    LoyoMGuerrero-PrestonRBraitM. Quantitative detection of Merkel cell virus in human tissues and possible mode of transmission. Int J Cancer2010;126;29912996.

    • Search Google Scholar
    • Export Citation
  • 46.

    NakajimaHTakaishiMYamamotoM. Screening of the specific polyoma virus as diagnostic and prognostic tools for Merkel cell carcinoma. J Dermatol Sci2009;56:211213.

    • Search Google Scholar
    • Export Citation
  • 47.

    NakamuraTSatoYWatanabeD. Nuclear localization of Merkel cell polyomavirus large T antigen in Merkel cell carcinoma. Virology2010;398:273279.

    • Search Google Scholar
    • Export Citation
  • 48.

    Sastre-GarauXPeterMAvrilMF. Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J Pathol2009;218:4856.

    • Search Google Scholar
    • Export Citation
  • 49.

    ShudaMAroraRKwunHJ. Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int J Cancer2009;125:12431249.

    • Search Google Scholar
    • Export Citation
  • 50.

    SihtoHKukkoHKoljonenV. Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst2009;101:938945.

    • Search Google Scholar
    • Export Citation
  • 51.

    TolstovYLPastranaDVFengH. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer2009;125:12501256.

    • Search Google Scholar
    • Export Citation
  • 52.

    TouzeAGaitanJMaruaniA. Merkel cell polyomavirus strains in patients with merkel cell carcinoma. Emerg Infect Dis2009;15:960962.

  • 53.

    VargaEKissMSzaboKKemenyL. Detection of Merkel cell polyomavirus DNA in Merkel cell carcinomas. Br J Dermatol2009;161:930932.

  • 54.

    WetzelsCTHoefnagelJGBakkersJM. Ultrastructural proof of polyomavirus in Merkel cell carcinoma tumour cells and its absence in small cell carcinoma of the lung. PLoS One2009;4:e4958.

    • Search Google Scholar
    • Export Citation
  • 55.

    WielandUMauchCKreuterA. Merkel cell polyomavirus DNA in persons without Merkel cell carcinoma. Emerg Infect Dis2009;15:14961498.

  • 56.

    WooKJChoiYLJungHS. Merkel cell carcinoma: our experience with seven patients in Korea and a literature review. J Plast Reconstr Aesthet Surg2010; in press.

    • Search Google Scholar
    • Export Citation
  • 57.

    RollisonDEBeckerJC. Association between Merkel cell polyomavirus and Merkel cell carcinoma. In:SondakVKMessinaJLZagerJS eds. Merkel Cell Carcinoma: A Multidisciplinary Approach. Imperial College Press; 2010.

    • Search Google Scholar
    • Export Citation
  • 58.

    AndresCBelloniBPuchtaU. Re: clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst2009;101:16551656.

    • Search Google Scholar
    • Export Citation
  • 59.

    BhatiaKGoedertJJModaliR. Immunological detection of viral large T antigen identifies a subset of Merkel cell carcinoma tumors with higher viral abundance and better clinical outcome. Int J Cancer2009; in press.

    • Search Google Scholar
    • Export Citation
  • 60.

    RaginCCTaioliE. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer2007;121:18131820.

    • Search Google Scholar
    • Export Citation
  • 61.

    LontAPKroonBKHorenblasS. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer2006;119:10781081.

    • Search Google Scholar
    • Export Citation
  • 62.

    ShudaMFengHKwunHJ. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A2008;105:1627216277.

    • Search Google Scholar
    • Export Citation
  • 63.

    StricklerHD. A multicenter evaluation of assays for detection of SV40 DNA and results in masked mesothelioma specimens. Cancer Epidemiol Biomarkers Prev2001;10:523532.

    • Search Google Scholar
    • Export Citation
  • 64.

    EngelsEAChenJHartgeP. Antibody responses to simian virus 40 T antigen: a case-control study of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev2005;14:521524.

    • Search Google Scholar
    • Export Citation
  • 65.

    KassemATechnauKKurzAK. Merkel cell polyomavirus sequences are frequently detected in nonmelanoma skin cancer of immunosuppressed patients. Int J Cancer2009;125:356361.

    • Search Google Scholar
    • Export Citation
  • 66.

    DworkinAMTsengSYAllainDC. Merkel cell polyomavirus in cutaneous squamous cell carcinoma of immunocompetent individuals. J Invest Dermatol2009;129:28682874.

    • Search Google Scholar
    • Export Citation
  • 67.

    RiddKYuSBastianBC. The presence of polyomavirus in non-melanoma skin cancer in organ transplant recipients is rare. J Invest Dermatol2009;129:250252.

    • Search Google Scholar
    • Export Citation
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