Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press5810.17650/2313-805X.2016.3.2.18-25REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИGenetic and epigenetic mechanisms of regulation of human papillomavirusГенетические и эпигенетические механизмы регуляции вирусов папиллом человекаVinokurovaS. V.ВинокуроваС. В.
Russian Federation
vinokourova@mail.ruResearch Institute of Carcinogenesis, N.N. Blokhin Russian Cancer Research Center, Ministry of Health of RussiaНИИ канцерогенеза ФГБУ «РОНЦ им. Н. Н. Блохина» Минздрава России24 Kashirskoe Shosse, Moscow, 115478, RussiaРоссия, 115478, Москва, Каширское шоссе, 24150520163218250706201607062016Copyright ©; 2016, Vinokurova S.V.Copyright ©; 2016, Винокурова С.В.2016Vinokurova S.V.Винокурова С.В.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/58

Infections with high-risk human papillomaviruses (HPV) are the etiological factor of certain types of human cancers in anogenital tract and head and neck cancers. Extensive epidemiological studies demonstrated the association of persistent high-risk HPV infection and the later development of cervical and other cancers. Experimental data using cell lines models and cervical cancers demonstrate that in more than 99 % of clinical samples the viral E6 and E7 genes are retained and expressed. These genes can transform human cells and inhibition of their expression in cancer cells results in loss of neoplastic growth properties. Molecular mechanisms of immortalization and transformation by E6 and E7 have extensively been investigated. However, the mechanism of E6 and E7 deregulation that triggers the shift from permissive infection to neoplastic transforming infection is still unclear. This review describes the current knowledge about the viral life cycle and discusses the molecular mechanisms that potentially allow the virus to escape its normal control and may trigger neoplastic progression. The molecular clarification of these events required for transformation of HPV-infected cells into cancer will provide a basis for conceptually novel diagnostic and therapeutic strategies and approaches.

human papillomavirushigh-risk papillomavirusHPV-associated cancercervical cancerviral genome integrationviral genome methylationвирус папилломы человекавирус папилломы высокого канцерогенного рискаHPV-ассоциированная опухольрак шейки маткиинтеграция вирусного геномаметилирование вирусного генома1. Bernard H. U., Burk R. D., Chen Z. et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 2010;401(1):70–9.Bernard H. U., Burk R. D., Chen Z. et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 2010;401(1):70–9.2. Munoz N., Bosch F. X., de Sanjose S. et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348(6):518–27.Munoz N., Bosch F. X., de Sanjose S. et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348(6):518–27.3. Doorbar J., Egawa N., Griffin H. et al. Human papillomavirus molecular biology and disease association. Rev Med Virol 2015;25:2–23.Doorbar J., Egawa N., Griffin H. et al. Human papillomavirus molecular biology and disease association. Rev Med Virol 2015;25:2–23.4. Doorbar J., Quint W., Banks L. et al. The biology and life-cycle of human papillomaviruses. Vaccine 2012;30:55–70.Doorbar J., Quint W., Banks L. et al. The biology and life-cycle of human papillomaviruses. Vaccine 2012;30:55–70.5. Kalantari M., Lee D., Calleja-Macias I. E. et al. Effects of cellular differentiation, chromosomal integration and 5-aza-2’ – deoxycytidine treatment on human papillomavirus-16 DNA methylation in cultured cell lines. Virology 2008;374(2):292–303.Kalantari M., Lee D., Calleja-Macias I. E. et al. Effects of cellular differentiation, chromosomal integration and 5-aza-2’ – deoxycytidine treatment on human papillomavirus-16 DNA methylation in cultured cell lines. Virology 2008;374(2):292–303.6. Goon P., Sonnex C., Jani P. et al. Recurrent respiratory papillomatosis: an overview of current thinking and treatment. Eur Arch Otorhinolaryngol 2008;265(2):147–51.Goon P., Sonnex C., Jani P. et al. Recurrent respiratory papillomatosis: an overview of current thinking and treatment. Eur Arch Otorhinolaryngol 2008;265(2):147–51.7. Howley P. M., Pfister H. J. Beta genus papillomaviruses and skin cancer. Virology 2015;479–480:290–6.Howley P. M., Pfister H. J. Beta genus papillomaviruses and skin cancer. Virology 2015;479–480:290–6.8. Howley P. M. Warts, cancer and ubiquitylation: lessons from the papillomaviruses. Trans Am Clin Climatol Assoc 2006;117:113–26.Howley P. M. Warts, cancer and ubiquitylation: lessons from the papillomaviruses. Trans Am Clin Climatol Assoc 2006;117:113–26.9. zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000;92:690–8.zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000;92:690–8.10. Chow L. T., Broker T. R., Steinberg B. M. The natural history of human papillomavirus infections of the mucosal epithelia. APMIS 2010;118(6–7):422–49.Chow L. T., Broker T. R., Steinberg B. M. The natural history of human papillomavirus infections of the mucosal epithelia. APMIS 2010;118(6–7):422–49.11. Schiller J. T., Day P. M., Kines R. C. Current understanding of the mechanism of HPV infection. Gynecol Oncol 2010;118:S12–7.Schiller J. T., Day P. M., Kines R. C. Current understanding of the mechanism of HPV infection. Gynecol Oncol 2010;118:S12–7.12. Doorbar J. Latent papillomavirus infections and their regulation. Curr Opin Virol 2013;3(4):416–21.Doorbar J. Latent papillomavirus infections and their regulation. Curr Opin Virol 2013;3(4):416–21.13. Doeberitz M., Vinokurova S. Host factors in HPV-related carcinogenesis: cellular mechanisms controlling HPV infections. Arch Med Res 2009;40(6):435–42.Doeberitz M., Vinokurova S. Host factors in HPV-related carcinogenesis: cellular mechanisms controlling HPV infections. Arch Med Res 2009;40(6):435–42.14. Kajitani N., Satsuka A., Kawate A., Sakai H. Productive lifecycle of human papillomaviruses that depends upon squamous epithelial differentiation. Front Microbiol 2012;3:152.Kajitani N., Satsuka A., Kawate A., Sakai H. Productive lifecycle of human papillomaviruses that depends upon squamous epithelial differentiation. Front Microbiol 2012;3:152.15. Thierry F. Transcriptional regulation of the papillomavirus oncogenes by cellular and viral transcription factors in cervical carcinoma. Virology 2009;384(2):375–9.Thierry F. Transcriptional regulation of the papillomavirus oncogenes by cellular and viral transcription factors in cervical carcinoma. Virology 2009;384(2):375–9.16. Demeret C., Desaintes C., Yaniv M., Thierry F. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes. J Virol 1997;71(12):9343–9.Demeret C., Desaintes C., Yaniv M., Thierry F. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes. J Virol 1997;71(12):9343–9.17. Dostatni N., Lambert P. F., Sousa R. et al. The functional BPV-1 E2 trans-activating protein can act as a repressor by preventing formation of the initiation complex. Genes Dev 1991;5(9):1657–71.Dostatni N., Lambert P. F., Sousa R. et al. The functional BPV-1 E2 trans-activating protein can act as a repressor by preventing formation of the initiation complex. Genes Dev 1991;5(9):1657–71.18. Dong G., Broker T. R., Chow L. T. Human papillomavirus type 11 E2 proteins repress the homologous E6 promoter by interfering with the binding of host transcription factors to adjacent elements. J Virol 1994;68(2):1115–27.Dong G., Broker T. R., Chow L. T. Human papillomavirus type 11 E2 proteins repress the homologous E6 promoter by interfering with the binding of host transcription factors to adjacent elements. J Virol 1994;68(2):1115–27.19. Rapp B., Pawellek A., Kraetzer F. et al. Cell-type-specific separate regulation of the E6 and E7 promoters of human papillomavirus type 6a by the viral transcription factor E2. J Virol 1997;71:6956–66.Rapp B., Pawellek A., Kraetzer F. et al. Cell-type-specific separate regulation of the E6 and E7 promoters of human papillomavirus type 6a by the viral transcription factor E2. J Virol 1997;71:6956–66.20. Steger G., Corbach S. Dose-dependent regulation of the early promoter of human papillomavirus type 18 by the viral E2 protein. J Virol 1997;71(1):50–8.Steger G., Corbach S. Dose-dependent regulation of the early promoter of human papillomavirus type 18 by the viral E2 protein. J Virol 1997;71(1):50–8.21. Hebner C. M., Laimins L. A. Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity. Rev Med Virol 2006;16(2):83–97.Hebner C. M., Laimins L. A. Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity. Rev Med Virol 2006;16(2):83–97.22. Cheng S., Schmidt-Grimminger D. C., Murant T. et al. Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev 1995;9(19):2335–49.Cheng S., Schmidt-Grimminger D. C., Murant T. et al. Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev 1995;9(19):2335–49.23. Bodily J., Laimins L. A. Persistence of human papillomavirus infection: keys to malignant progression. Trends Microbiol 2011;19(1):33–9.Bodily J., Laimins L. A. Persistence of human papillomavirus infection: keys to malignant progression. Trends Microbiol 2011;19(1):33–9.24. Doorbar J. The papillomavirus life cycle. J Clin Virol 2005;32(Suppl 1):7–15.Doorbar J. The papillomavirus life cycle. J Clin Virol 2005;32(Suppl 1):7–15.25. Meyers C., Mayer T. J., Ozbun M. A. Synthesis of infectious human papillomavirus type 18 in differentiating epithelium transfected with viral DNA. J Virol 1997;71(10):7381–6.Meyers C., Mayer T. J., Ozbun M. A. Synthesis of infectious human papillomavirus type 18 in differentiating epithelium transfected with viral DNA. J Virol 1997;71(10):7381–6.26. Ozbun M. A., Meyers C. Characterization of late gene transcripts expressed during vegetative replication of human papillomavirus type 31b. J Virol 1997;71(7):5161–72.Ozbun M. A., Meyers C. Characterization of late gene transcripts expressed during vegetative replication of human papillomavirus type 31b. J Virol 1997;71(7):5161–72.27. Gariglio P., Gutierrez J., Cortes E., Vázquez J. The role of retinoid deficiency and estrogens as cofactors in cervical cancer. Arch Med Res 2009;40(6):449–65.Gariglio P., Gutierrez J., Cortes E., Vázquez J. The role of retinoid deficiency and estrogens as cofactors in cervical cancer. Arch Med Res 2009;40(6):449–65.28. Duensing A., Spardy N., Chatterjee P. et al. Centrosome overduplication, chromosomal instability, and human papillomavirus oncoproteins. Environ Mol Mutagen 2009;50(8):741–7.Duensing A., Spardy N., Chatterjee P. et al. Centrosome overduplication, chromosomal instability, and human papillomavirus oncoproteins. Environ Mol Mutagen 2009;50(8):741–7.29. Moody C. A., Laimins L. A. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 2010;10(8):550–60.Moody C. A., Laimins L. A. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 2010;10(8):550–60.30. Pett M., Coleman N. Integration of highrisk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007;212(4):356–67.Pett M., Coleman N. Integration of highrisk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007;212(4):356–67.31. Woodman C. B., Collins S. I., Young L. S. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer 2007;7(1):11–22.Woodman C. B., Collins S. I., Young L. S. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer 2007;7(1):11–22.32. Vinokurova S., Wentzensen N., Kraus I. et al. Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res 2008;68(1):307–13.Vinokurova S., Wentzensen N., Kraus I. et al. Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res 2008;68(1):307–13.33. Klaes R., Woerner S. M., Ridder R. et al. Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 1999;59(24):6132–6.Klaes R., Woerner S. M., Ridder R. et al. Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 1999;59(24):6132–6.34. Samoylova E. V., Shaikhaiev G. O., Petrov S. V. et al. HPV infection in cervicalcancer cases in Russia. Int J Cancer 1995;61(3):337–41.Samoylova E. V., Shaikhaiev G. O., Petrov S. V. et al. HPV infection in cervicalcancer cases in Russia. Int J Cancer 1995;61(3):337–41.35. Arias-Pulido H., Peyton C. L., Joste N. E. et al. Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol 2006;44(5):1755–62.Arias-Pulido H., Peyton C. L., Joste N. E. et al. Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol 2006;44(5):1755–62.36. Sano T., Oyama T., Kashiwabara K. et al. Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 1998;153(6):1741–8.Sano T., Oyama T., Kashiwabara K. et al. Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 1998;153(6):1741–8.37. Wentzensen N., von Knebel Doeberitz M. Biomarkers in cervical cancer screening. Dis Markers 2007;23(4):315–30.Wentzensen N., von Knebel Doeberitz M. Biomarkers in cervical cancer screening. Dis Markers 2007;23(4):315–30.38. Klaes R., Friedrich T., Spitkovsky D. et al. Overexpression of p16 (INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 2001;92(2):276–84.Klaes R., Friedrich T., Spitkovsky D. et al. Overexpression of p16 (INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 2001;92(2):276–84.39. Bird A. DNA methylation de novo. Science 1999;286(5448):2287–8.Bird A. DNA methylation de novo. Science 1999;286(5448):2287–8.40. Bird A. P. The relationship of DNA methylation to cancer. Cancer Surv 1996;28:87–101.Bird A. P. The relationship of DNA methylation to cancer. Cancer Surv 1996;28:87–101.41. Boyes J., Bird A. DNA methylation inhibits transcription indirectly via a methyl- CpG binding protein. Cell 1991;64:1123–34.Boyes J., Bird A. DNA methylation inhibits transcription indirectly via a methyl- CpG binding protein. Cell 1991;64:1123–34.42. Kass S. U., Pruss D., Wolffe A. P. How does DNA methylation repress transcription? Trends Genet 1997;13:444–9.Kass S. U., Pruss D., Wolffe A. P. How does DNA methylation repress transcription? Trends Genet 1997;13:444–9.43. Siegfried Z., Eden S., Mendelsohn M. et al. DNA methylation represses transcription in vivo. Nat Genet 1999;22(2):203–6.Siegfried Z., Eden S., Mendelsohn M. et al. DNA methylation represses transcription in vivo. Nat Genet 1999;22(2):203–6.44. Shiota K. DNA methylation profiles of CpG islands for cellular differentiation and development in mammals. Cytogenet Genome Res 2004;105(2–4):325–34.Shiota K. DNA methylation profiles of CpG islands for cellular differentiation and development in mammals. Cytogenet Genome Res 2004;105(2–4):325–34.45. Lund A. H., van Lohuizen M. Epigenetics and cancer. Genes Dev 2004;18(19):2315–35.Lund A. H., van Lohuizen M. Epigenetics and cancer. Genes Dev 2004;18(19):2315–35.46. Baylin S. B., Ohm J. E. Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 2006;6(2):107–16.Baylin S. B., Ohm J. E. Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 2006;6(2):107–16.47. Shenker N., Flanagan J. M. Intragenic DNA methylation: implications of this epigenetic mechanism for cancer research. Br J Cancer 2012;106(2):248–53.Shenker N., Flanagan J. M. Intragenic DNA methylation: implications of this epigenetic mechanism for cancer research. Br J Cancer 2012;106(2):248–53.48. Maunakea A. K., Nagarajan R. P., Bilenky M. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010;466(7303):253–7.Maunakea A. K., Nagarajan R. P., Bilenky M. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010;466(7303):253–7.49. Lorincz M. C., Dickerson D. R., Schmitt M., Groudine M. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat Struct Mol Biol 2004;11(11):1068–75.Lorincz M. C., Dickerson D. R., Schmitt M., Groudine M. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat Struct Mol Biol 2004;11(11):1068–75.50. Choi J. K., Bae J. B., Lyu J. et al. Nucleosome deposition and DNA methylation at coding region boundaries. Genome Biol 2009;10(9):R89.Choi J. K., Bae J. B., Lyu J. et al. Nucleosome deposition and DNA methylation at coding region boundaries. Genome Biol 2009;10(9):R89.51. Diniz S. N., Pendeloski K. P., Morgun A. et al. Tissue-specific expression of IL-15RA alternative splicing transcripts and its regulation by DNA methylation. Eur Cytokine Netw 2010;21(4):308–18.Diniz S. N., Pendeloski K. P., Morgun A. et al. Tissue-specific expression of IL-15RA alternative splicing transcripts and its regulation by DNA methylation. Eur Cytokine Netw 2010;21(4):308–18.52. Oberdoerffer S. A conserved role for intragenic DNA methylation in alternative pre-mRNA splicing. Transcription 2012;3(3):106–9.Oberdoerffer S. A conserved role for intragenic DNA methylation in alternative pre-mRNA splicing. Transcription 2012;3(3):106–9.53. Shukla S., Kavak E., Gregory M. et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 2011;479(7371):74–9.Shukla S., Kavak E., Gregory M. et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 2011;479(7371):74–9.54. Salem C., Liang G., Tsai Y. C. et al. Progressive increases in de novo methylation of CpG islands in bladder cancer. Cancer Res 2000;60(9):2473–6.Salem C., Liang G., Tsai Y. C. et al. Progressive increases in de novo methylation of CpG islands in bladder cancer. Cancer Res 2000;60(9):2473–6.55. Smith I. M., Mydlarz W. K., Mithani S. K., Califano J. A. DNA global hypomethylation in squamous cell head and neck cancer associated with smoking, alcohol consumption and stage. Int J Cancer 2007;121(8):1724–8.Smith I. M., Mydlarz W. K., Mithani S. K., Califano J. A. DNA global hypomethylation in squamous cell head and neck cancer associated with smoking, alcohol consumption and stage. Int J Cancer 2007;121(8):1724–8.56. Karlin S., Doerfler W., Cardon L. R. Why is CpG suppressed in the genomes of virtually all small eukaryotic viruses but not in those of large eukaryotic viruses? J Virol 1994;68(5):2889–97.Karlin S., Doerfler W., Cardon L. R. Why is CpG suppressed in the genomes of virtually all small eukaryotic viruses but not in those of large eukaryotic viruses? J Virol 1994;68(5):2889–97.57. Galvan S. C., Martinez-Salazar M., Galvan V. M. et al. Analysis of CpG methylation sites and CGI among human papillomavirus DNA genomes. BMC Genomics 2011;12:580.Galvan S. C., Martinez-Salazar M., Galvan V. M. et al. Analysis of CpG methylation sites and CGI among human papillomavirus DNA genomes. BMC Genomics 2011;12:580.58. Sanchez I. E., Dellarole M., Gaston K., de Prat Gay G. Comprehensive comparison of the interaction of the E2 master regulator with its cognate target DNA sites in 73 human papillomavirus types by sequence statistics. Nucleic Acids Res 2008;36(3):756–69.Sanchez I. E., Dellarole M., Gaston K., de Prat Gay G. Comprehensive comparison of the interaction of the E2 master regulator with its cognate target DNA sites in 73 human papillomavirus types by sequence statistics. Nucleic Acids Res 2008;36(3):756–69.59. Rosl F., Arab A., Klevenz B. et al. The effect of DNA methylation on gene regulation of human papillomaviruses. J Gen Virol 1993;74(Pt 5):791–801.Rosl F., Arab A., Klevenz B. et al. The effect of DNA methylation on gene regulation of human papillomaviruses. J Gen Virol 1993;74(Pt 5):791–801.60. Thain A., Jenkins O., Clarke A. R., Gaston K. CpG methylation directly inhibits binding of the human papillomavirus type 16 E2 protein to specific DNA sequences. J Virol 1996;70(10):7233–5.Thain A., Jenkins O., Clarke A. R., Gaston K. CpG methylation directly inhibits binding of the human papillomavirus type 16 E2 protein to specific DNA sequences. J Virol 1996;70(10):7233–5.61. Kim K., Garner-Hamrick P. A., Fisher C. et al. Methylation patterns of papillomavirus DNA, its influence on E2 function, and implications in viral infection. J Virol 2003;77(23):12450–9.Kim K., Garner-Hamrick P. A., Fisher C. et al. Methylation patterns of papillomavirus DNA, its influence on E2 function, and implications in viral infection. J Virol 2003;77(23):12450–9.62. Fernandez A. F., Rosales C., Lopez-Nieva P. et al. The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Res 2009;19(3):438–51.Fernandez A. F., Rosales C., Lopez-Nieva P. et al. The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Res 2009;19(3):438–51.63. Bhattacharjee B., Sengupta S. CpG methylation of HPV 16 LCR at E2 binding site proximal to P97 is associated with cervical cancer in presence of intact E2. Virology 2006;354(2):280–5.Bhattacharjee B., Sengupta S. CpG methylation of HPV 16 LCR at E2 binding site proximal to P97 is associated with cervical cancer in presence of intact E2. Virology 2006;354(2):280–5.64. Brandsma J. L., Sun Y., Lizardi P. M. et al. Distinct human papillomavirus type 16 methylomes in cervical cells at different stages of premalignancy. Virology 2009;389(1–2):100–7.Brandsma J. L., Sun Y., Lizardi P. M. et al. Distinct human papillomavirus type 16 methylomes in cervical cells at different stages of premalignancy. Virology 2009;389(1–2):100–7.65. Kalantari M., Calleja-Macias I. E., Tewari D. et al. Conserved methylation patterns of human papillomavirus type 16 DNA in asymptomatic infection and cervical neoplasia. J Virol 2004;78(23):12762–72.Kalantari M., Calleja-Macias I. E., Tewari D. et al. Conserved methylation patterns of human papillomavirus type 16 DNA in asymptomatic infection and cervical neoplasia. J Virol 2004;78(23):12762–72.66. Kalantari M., Chase D. M., Tewari K. S., Bernard H. U. Recombination of human papillomavirus-16 and host DNA in exfoliated cervical cells: a pilot study of L1 gene methylation and chromosomal integration as biomarkers of carcinogenic progression. J Med Virol 2010;82(2):311–20.Kalantari M., Chase D. M., Tewari K. S., Bernard H. U. Recombination of human papillomavirus-16 and host DNA in exfoliated cervical cells: a pilot study of L1 gene methylation and chromosomal integration as biomarkers of carcinogenic progression. J Med Virol 2010;82(2):311–20.67. Mirabello L., Schiffman M., Ghosh A. et al. Elevated methylation of HPV 16 DNA is associated with the development of high grade cervical intraepithelial neoplasia. Int J Cancer 2013;132(6):1412–22.Mirabello L., Schiffman M., Ghosh A. et al. Elevated methylation of HPV 16 DNA is associated with the development of high grade cervical intraepithelial neoplasia. Int J Cancer 2013;132(6):1412–22.68. Mirabello L., Sun C., Ghosh A. et al. Methylation of human papillomavirus type 16 genome and risk of cervical precancer in a Costa Rican population. J Natl Cancer Inst 2012;104(7):556–65.Mirabello L., Sun C., Ghosh A. et al. Methylation of human papillomavirus type 16 genome and risk of cervical precancer in a Costa Rican population. J Natl Cancer Inst 2012;104(7):556–65.69. Vinokurova S., von Knebel Doeberitz M. Differential methylation of the HPV 16 upstream regulatory region during epithelial differentiation and neoplastic transformation. PLoS One 2011;6(9):e24451.Vinokurova S., von Knebel Doeberitz M. Differential methylation of the HPV 16 upstream regulatory region during epithelial differentiation and neoplastic transformation. PLoS One 2011;6(9):e24451.70. Chaiwongkot A., Vinokurova S., Pientong C. et al. Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions. Int J Cancer 2013;132(9):2087–94.Chaiwongkot A., Vinokurova S., Pientong C. et al. Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions. Int J Cancer 2013;132(9):2087–94.71. Wooldridge T. R., Laimins L. A. Regulation of human papillomavirus type 31 gene expression during the differentiationdependent life cycle through histone modifications and transcription factor binding. Virology 2008;374(2):371–80.Wooldridge T. R., Laimins L. A. Regulation of human papillomavirus type 31 gene expression during the differentiationdependent life cycle through histone modifications and transcription factor binding. Virology 2008;374(2):371–80.