Investigation of three oncogenic epitheliotropic viruses shows human papillomavirus in association with non-melanoma skin cancer

Abstract

Non-melanoma skin cancers (NMSC) share similar risk factors with other virus-related cancers, despite the lack of proved causal association between viral infection and NMSC development. We investigated the presence of Merkel cell polyomavirus (MCPyV), Epstein-Barr virus (EBV), and human papillomavirus (HPV) DNA in 83 NMSC fresh-frozen and 16 non-cancerous skin biopsies and evaluated viral infection according to demographical data, histopathological diagnosis, and ultraviolet exposure. Our results showed that 75% of NMSC biopsies were positive for at least one out of three viruses, whereas only 38% of non-cancerous skin biopsies were positive (p = 0.02). Notably, HPV detection was frequent in NMSC (43%) and nearly absent (one sample, 6.7%) in non-cancerous biopsies (p = 0.007). MCPyV was associated with sites of higher exposure to ultraviolet radiation (p = 0.010), while EBV was associated with a compromised immune system (p = 0.032). Our study showed that HPV was strongly associated with NMSC while EBV and MCPyV with other risk factors. Though further studies are required to elucidate the role of viral infection in NMSC development and management, this study supports the possible role of oncogenic viruses in skin cancers, especially HPV.

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References

  1. 1.

    INCA (2017) Estimativa2018. Incidencia de cáncer no Brasil

  2. 2.

    Katalinic A, Kunze U, Schafer T (2003) Epidemiology of cutaneous melanoma and nonmelanoma skin cancer in Schleswig-Holstein, Germany: incidence, clinical subtypes, tumour stages and localization (epidemiology of skin cancer). Br J Dermatol. https://doi.org/10.1111/j.1365-2133.2003.05554.x

  3. 3.

    Eisemann N, Waldmann A, Geller AC et al (2014) Non-melanoma skin cancer incidence and impact of skin cancer screening on incidence. J Invest Dermatol 134:43–50. https://doi.org/10.1038/jid.2013.304

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Feng H, Shuda M, Chang Y, Moore PS (2008) Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 5866:1096–1100. https://doi.org/10.1126/science.1152586

    Article  CAS  Google Scholar 

  5. 5.

    International Agency for Cancer Research (IARC) Monograph Working Group. Special report: policy a review of human carcinogens—part D: radiation. (2009) The Lancet Oncology.

  6. 6.

    Chen AC, Halliday GM, Damian DL (2013) Non-melanoma skin cancer: carcinogenesis e chemoprevention. Pathology 45:331–341. https://doi.org/10.1097/PAT.0b013e32835f515c

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Montagna M, Carlisle K (1991) The architecture of black e white facial skin. Am Acad Dermatol 6:929–937

    Article  Google Scholar 

  8. 8.

    Singh SK, Kurfurst R, Nizard C et al (2010) Melanin transfer in human skin cells is mediated by filopodia--a model for homotypic and heterotypic lysosome-related organelle transfer. FASEB J 24:3756–3769. https://doi.org/10.1096/fj.10-159046

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Tessari G, Girolomoni G (2012) Nonmelanoma skin cancer in solid organ transplant recipients: update on epidemiology, risk factors, and Management. Dermatol Surg 8:1622–1630. https://doi.org/10.1111/j.1524-4725.2012.02520.x.

    Article  Google Scholar 

  10. 10.

    Foulongne V, Sauvage V, Hebert C et al (2012) Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing. PLoS One 7:e38499. https://doi.org/10.1371/journal.pone.0038499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Bouwes Bavinck JN, Feltkamp MCW, Green AC et al (2017) Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: a multicenter, prospective cohort study. Am J Transplant. https://doi.org/10.1111/ajt.14537

  12. 12.

    Bernat-García J, Suárez-Varela MM, Vilata-Corell JJ, Marquina-Vila A (2014) Detection of human papillomavirus in nonmelanoma skin cancer lesions and healthy perilesional skin in kidney transplant recipients and immunocompetent patients. Actas Dermosifiliogr 105:286–294. https://doi.org/10.1016/j.adengl.2013.10.008

    Article  PubMed  Google Scholar 

  13. 13.

    Bofill-Mas S, Rodriguez-Manzano J, Calgua B et al (2010) New described human polyomaviruses Merkel cell, KI and WU are present in urban sewage and may represent potential environmental contaminants. Virol J 141. https://doi.org/10.1186/1743-422X-7-141

  14. 14.

    Shotelersuk K, Khorprasert C, Sakdikul S et al (2000) Epstein-Barr virus DNA in serum/plasma as a tumor marker for nasopharyngeal cancer. Clin Cancer Res 3:1046–1051

    Google Scholar 

  15. 15.

    Bauer HM, Greer CE, Manos MM (1992) Determination of genital human papillomavirus infection using consensus PCR. In: Herrington CS, McGee JOD (eds) Diagnostic molecular pathology: a practical approach. Oxford University Press, Oxford, United Kingdom, pp 132–152

    Google Scholar 

  16. 16.

    Escutia B, Ledesma E, Serra-Guillen C et al (2011) Detection of human papilloma virus in normal skin and in superficial and nodular basal cell carcinomas in immunocompetent subjects. J Eur Acad Dermatol Venereol 25:832–838. https://doi.org/10.1111/j.1468-3083.2010.03875.x

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Zaravinos A, Kanellou P, Spandidos DA (2010) Viral DNA detection and RAS mutations in actinic keratosis and nonmelanoma skin cancers. Br J Dermatol 162:325–331. https://doi.org/10.1111/j.1365-2133.2009.09480.x

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Ramezani M, Sadeghi M (2017) Human papilloma virus infection in basal cell carcinoma of the skin: a systematic review and meta-analysis study. Pol J Pathol 68(4):330–342. https://doi.org/10.5114/pjp.2017.73929

    Article  PubMed  Google Scholar 

  19. 19.

    Chahoud J, Semaan A, Chen Y et al (2016) Association between β-genus human papillomavirus and cutaneous squamous cell carcinoma in immunocompetent individuals—ameta-analysis. JAMA Dermatol 152(12):1354–1364. https://doi.org/10.1001/jamadermatol.2015.4530

    Article  PubMed  Google Scholar 

  20. 20.

    Wallace NA, Robinson K, Howie HL, Galloway DA (2012) HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. PLoS Pathog 8:e1002807. https://doi.org/10.1371/journal.ppat.1002807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Wallace NA, Robinson K, Galloway DA (2014) Beta human papillomavirus E6 expression inhibits stabilization of p53 and increases tolerance of genomic instability. J Virol 88:6112–6127. https://doi.org/10.1128/JVI.03808-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Nichols AJ, Gonzalez A, Clark ES et al (2018) Combined systemic and intratumoral administration of human papillomavirus vaccine to treat multiple cutaneous basaloid squamous cell carcinomas. JAMA Dermatol 154(8):927–930. https://doi.org/10.1001/jamadermatol.2018.1748

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Arron ST, Jennings L, Nindl I et al (2011) Viral Working Group of the International Transplant Skin Cancer Collaborative (ITSCC) & Skin Care in Organ Transplant Patients, Europe (SCOPE). Viral oncogenesis and its role in nonmelanoma skin cancer. Br J Dermat 164:1201–1213. https://doi.org/10.1111/j.1365-2133.2011.10322.x

    Article  CAS  Google Scholar 

  24. 24.

    International Agency for Cancer Research (IARC) workGroup (2012) Volume 100D: solar and ultraviolet radiation, IARC Monographs.

  25. 25.

    Wang J, Aldabagh B, Yu J, Arron ST (2014) Role of human papillomavirus in cutaneous squamous cell carcinoma: a meta-analysis. J Am Acad Dermatol 70:621–629. https://doi.org/10.1016/j.jaad.2014.01.857

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Moore PS, Chang Y (2010) Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer 10:878–889. https://doi.org/10.1038/nrc2961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Baez CF, da Rocha WM, Afonso LA et al (2015) First report of three major oncogenic viruses: human papillomavirus, Epstein-Barr virus and Merkel cell polyomavirus in penile cancer. J Infect Dis Ther 4. https://doi.org/10.4172/2332-0877.1000233

  28. 28.

    Feltkamp MC, Broer R, di Summa FM et al (2003) Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer. Cancer Res 63:2695–2700

    CAS  PubMed  Google Scholar 

  29. 29.

    Iannacone MR, Wang W, Stockwell HG et al (2012) Sunlight exposure and cutaneous human papillomavirus seroreactivity in basal cell and squamous cell carcinomas of the skin. J Infect Dis 206:399–406

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Meyer T, Arndt R, Christophers E, Stockfleth E (2006) Frequency and Spectrum of HPV types detected in cutaneous squamous-cell carcinomas depend on the HPV detection system: acomparison of four PCR assays. Dermat 201:204–211

    Article  Google Scholar 

  31. 31.

    Forslund O, Antonsson A, Nordin P, Stenquist B, Hansson BG (1999) A broad range of human papillomavirus types detected with a general PCR method suitable for analysis of cutaneous tumours and normal skin. J Gen Virol 80:2437–2443

    Article  CAS  Google Scholar 

Download references

Funding

This paper has been partially supported by FAPERJ (Rio de Janeiro Research Foundation). This study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.

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Correspondence to Rafael Brandão Varella.

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The authors declare that they haveno conflict of interest.

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The study was approved by the University Hospital Ethical Committee (protocol 608.880/2014). Informed consent was obtained from all individual participants included in the study.

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Baez, C.F., Gonçalves, M.T.V., da Rocha, W.M. et al. Investigation of three oncogenic epitheliotropic viruses shows human papillomavirus in association with non-melanoma skin cancer. Eur J Clin Microbiol Infect Dis 38, 1129–1133 (2019). https://doi.org/10.1007/s10096-019-03508-z

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Keywords

  • Skin cancer
  • Oncogenic viruses
  • Viral detection
  • Biopsy