Skip to main content
SpringerLink
Log in

DNA Methylation of Human Papillomavirus Genomes During Infection and Cancer Progression

  • Chapter
  • First Online:
Epigenetics of Infectious Diseases

Part of the book series: Epigenetics and Human Health ((EHH))

  • 1022 Accesses

Abstract

Human papillomaviruses (HPVs) are important pathogens, as they are the cause of all cervical cancers and of subsets of vulval, anal, oral, and penile cancers. The viral genome is an 8 kb double-stranded circular DNA, which can replicate in various types of epithelial cells. HPV DNA shows changes of its methylation profile during the viral life cycle, namely “sporadic” and “polymorphic” DNA methylation associated with low transcription in basal cells of epithelia, and a lack of methylation in suprabasal cells associated with strong transcription. While these epigenetic changes of HPV DNA during the viral life cycle are still poorly understood, it has emerged that during progression of low-grade precursor lesions to malignant carcinomas, the HPV DNA becomes hypermethylated, probably since the viral genome recombines with the chromosomal DNA of the infected host cell. This methylation signal is intensely studied as a candidate biomarker for the diagnosis of HPV-associated lesions that have the potential to progress to cancer.

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

Access this chapter

Log in via an institution
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

References

  • Arias-Pulido H, Peyton CL, Joste NE, Vargas H, Wheeler CM (2006) Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol 44:1755–1762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Badal V, Chuang LSH, Badal S, Tang E, Villa LL, Wheeler CM, Li BFL, Bernard HU (2003) CpG methylation of human papillomavirus-16 DNA in cervical cancer cell lines and in clinical specimens: genomic hypomethylation correlates with carcinogenic progression. J Virol 77:6227–6234

    Article  PubMed  PubMed Central  Google Scholar 

  • Badal S, Badal V, Calleja-Macias IE, Kalantari M, Chuang LSH, Li BFL, Bernard HU (2004) The human papillomavirus-18 genome is efficiently targeted by cellular DNA methylation. Virology 324:483–492

    Article  CAS  PubMed  Google Scholar 

  • Balderas-Loaeza A, Anaya-Saavedra G, Ramirez-Amador VA, Guido-Jimenez MC, Kalantari M, Calleja-Macias IE, Bernard HU, Garcia-Carranca A (2007) Human papillomavirus-16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas. Int J Cancer 120:2165–2169

    Article  CAS  PubMed  Google Scholar 

  • Bergvall M, Melendy T, Archambault J (2013) The E1 proteins. Virology 445:35–56

    Article  CAS  PubMed  Google Scholar 

  • Bernard HU (2013) Regulatory elements in the papillomavirus genome. Virology 445:197–204

    Article  CAS  PubMed  Google Scholar 

  • Bernard HU, Burk RD, Chen Z, van Doorslaer K, zur Hausen H, de Villiers EM (2010) Classification of papillomaviruses based on 189 PV types and proposal of taxonomic amendments. Virology 401:70–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhattacharjee B, Sengupta S (2006) CpG methylation of HPV16 LCR at E2 binding site proximal to P97 is associated with cervical cancer in the presence of intact E2. Virology 354:280–285

    Article  CAS  PubMed  Google Scholar 

  • Bodily JM, Mehta KP, Laimins LA (2011) Human papillomavirus E7 enhances hypoxia-inducible factor 1-mediated transcription by inhibiting binding of histone deacetylases. Cancer Res 71:1187–1195

    Article  CAS  PubMed  Google Scholar 

  • Brandsma JL, Sun Y, Lizardi PM, Tuck DP, Zelterman D, Haines GK, Martel M, Harigopal M, Schofield K, Neapolitano M (2009) Distinct human papillomavirus type 16 methylomes in cervical cells at different stages of premalignancy. Virology 389:100–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brandsma JL, Harigopal M, Kiviat NB, Sun Y, Deng Y, Zelterman D, Lizardi PM, Shabanova VR, Levi A, Yaping T, Hu X, Feng Q (2014) Methylation of twelve CpGs in human papillomavirus type 16 (HPV16) as an informative biomarker for the triage of women positive for HPV16 infection. Cancer Prev Res 7:526–533

    Article  CAS  Google Scholar 

  • Bryant D, Onions T, Raybold R, Jones S, Tristram A, Hibbitts S, Fiander S, Powell N (2014) Increased methylation of human papillomavirus type 16 correlates with viral integration in vulval intraepithelial neoplasia. J Clin Virol 61:393–399

    Article  CAS  PubMed  Google Scholar 

  • Buck CB, Day PM, Trus BL (2013) The papillomavirus major capsid protein L1. Virology 445:169–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burgers WA, Blanchon L, Pradhan S, de Launoit Y, Kouzarides T, Fuks F (2007) Viral oncoproteins target the DNA methyltransferases. Oncogene 26:1650–1655

    Article  CAS  PubMed  Google Scholar 

  • Chaiwongkot A, Vinokurova S, Pientong C, Ekalaksananan T, Kongyingyoes B, Kleebkaow P, Chumworathayi B, Patarapadungkit N, Reuschenbach M, von Knebel Doeberitz M (2013) Differential methylation of E2 binding sites in episomal and integrated HPV16 genomes in preinvasive and invasive cervical lesions. Int J Cancer 132:2087–2094

    Article  CAS  PubMed  Google Scholar 

  • Clarke MA, Wentzensen N, Mirabello L, Ghosh A, Wacholder S, Harari A, Lorincz A, Schiffman M, Burk RD (2012) Human papillomavirus DNA methylation as a potential biomarker for cervical cancer. Cancer Epidemiol Biomark Prev 21:2125–2137

    Article  CAS  Google Scholar 

  • D’Costa ZJ, Jolly C, Androphy EJ, Mercer A, Matthews CM, Hibma MH (2012) Transcriptional repression of E-cadherin by human papillomavirus type 16 E6. PLoS One 7:e48954

    Article  PubMed  PubMed Central  Google Scholar 

  • Dörfler W, Remus R, Müller K, Hohlweg U, Schubbert R (2001) The fate of foreign DNA in mammalian cells and organisms. Dev Biol 106:89–97

    Google Scholar 

  • Edwards JR, O’Donnell AH, Rollins RA, Peckham HE, Lee C, Milekic MH, Chanrion B, Fu Y, Su T, Hibshoosh H, Gingrich JA, Haghighi F, Nutter R, Bestor TH (2010) Chromatin and sequence features that define the fine and gross structure of genomic methylation patterns. Genome Res 20:972–980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frimer M, McAndrew T, Smith B, Harari A, Chen Z, Mirabello L, Wentzensen N, Goldberg GL, Rodriguez AZ, Schiffman M, Burk RD (2015) HPV16 CpG methyl-haplotypes are associated with cervix precancer and cancer in the Guanacaste natural history study. Gynecol Oncol 138:94–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hernandez JM, Siegel EM, Riggs B, Eschrich S, Elahi A, Qu X, Ajidahun A, Berglund A, Coppola D, Grady WM, Giuliano AR, Shibata D (2012) DNA methylation profiling across the spectrum of HPV-associated anal squamous neoplasia. PLoS One 7:e50533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsu CH, Peng KL, Jhang HC, Lin CH, Wu SY, Chiang CM, Lee SC, Yu WC, Juan LJ (2012) The HPV E6 oncoprotein targets histone methyltransferases for modulating specific gene transcription. Oncogene 31:2335–2349

    Article  CAS  PubMed  Google Scholar 

  • Jitesh PV, Risk JM, Schache AG, Dhanda J, Lane B, Liloglou T, Shaw RJ (2013) The epigenetic landscape of oral squamous cell carcinoma. Br J Cancer 108:370–379

    Article  Google Scholar 

  • Johannsen E, Lambert PF (2013) Epigenetics of human papillomaviruses. Virology 445:205–212

    Article  CAS  PubMed  Google Scholar 

  • Kalantari M, Blennow E, Hagmar B, Johannson B (2001) Physical state of HPV16 and chromosomal mapping of the integrated form in cervical carcinomas. Diagn Mol Pathol 10:46–54

    Article  CAS  PubMed  Google Scholar 

  • Kalantari M, Calleja-Macias IE, Tewari K, Hagmar B, Barrera-Saldana HA, Wiley DJ, Bernard HU (2004) Conserved methylation patterns of human papillomavirus-16 DNA in asymptomatic infection and cervical neoplasia. J Virol 78:12762–12772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalantari M, Lee D, Calleja-Macias IE, Lambert PF, Bernard HU (2008a) Effects of cellular differentiation, chromosomal integration and treatment by 5′-deoxy-2′ azacytidine on human papillomavirus-16 DNA methylation in cultured cell lines. Virology 374:292–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalantari M, Villa LL, Calleja-Macias IE, Bernard HU (2008b) Human papillomavirus-16 and 18 in penile carcinomas: DNA methylation, chromosomal recombination, and genomic variation. Int J Cancer 123:1832–1840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalantari M, Osann K, Calleja-Macias IE, Kim S, Yan B, Jordan S, Chase DM, Tewari KS, Bernard HU (2014) Methylation of human papillomavirus 16, 18, 31 and 45 L2 and L1 genes and the cellular DAPK gene: considerations fur use as biomarkers of the progression of cervical neoplasia. Virology 448:314–322

    Article  CAS  PubMed  Google Scholar 

  • Kim K, Garner-Hamrick RP, Fisher C, Lee D, Lambert PF (2003) Methylation of patterns of papillomavirus DNA, its influence on E2 function, and implications in viral infection. J Virol 77:12450–12459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laurson J, Khan S, Chung R, Cross K, Raj K (2010) Epigenetic repression of E-cadherin by human papillomavirus 17 E7 protein. Carcinogenesis 31:918–926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Louvanto K, Franco EL, Ramanakumar AV, Vasiljevic N, Scibior-Bentkowska D, Koushik A, Cusick J, Coutlee F, Lorincz AT, Biomarkers of Cervical Cancer Risk Study Team (2015) Methylation of viral and host genes and severity of cervical lesions associated with human papillomavirus type 16. Int J Cancer 136:E638–E645

    Article  CAS  PubMed  Google Scholar 

  • McBride AA (2013) The papillomavirus E2 proteins. Virology 445:57–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mine KL, Shulzehenko N, Yambartsev A, Rochman M, Sanson GFO, Lando M, Varma S, Skinner J, Volfovsky N, Deng T, Brenna SMF, Carvalho CRN, Ribalta JCL, Bustin M, Matzinger P, Silva IDCG, Lyng H, Gerbase-DeLima M, Morgun A (2013) Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer. Nat Commun 4:1806–1810

    Article  PubMed  PubMed Central  Google Scholar 

  • Mirabello L, Schiffman M, Ghosh A, Rodriguez AC, Vasilijevic N, Wentzensen N, Herrero R, Hildesheim A, Wacholder S, Scibior-Bentkowska D, Burk RD, Lorincz AT (2013) Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia. Int J Cancer 132:1412–1422

    Article  CAS  PubMed  Google Scholar 

  • Mirabello L, Frimer M, Harari A, McAndrew T, Smith B, Chen Z, Wentzensen N, Wacholder S, Castle PE, Raine-Bennett T, Schiffman M, Burk RD (2015) HPV16 methyl-haplotypes determined by a novel next-generation sequencing methods are associated with cervical precancer. Int J Cancer 136:E146–E153

    Article  CAS  PubMed  Google Scholar 

  • Murakami I, Fujii T, Dan K, Saito M, Ohno A, Iwata T, Aoki D (2013) Methylation of human papillomavirus 52 and 58 is a candidate biomarker in cervical neoplasia. J Clin Virol 58:149–154

    Article  CAS  PubMed  Google Scholar 

  • Park IS, Chang X, Loyo M, Wu G, Chuang A, Kim M, Chai YK, Lyford-Pike S, Westra WH, Saunders JR, Sidransky D, Pai S (2011) Characterization of the methylation patterns in human papillomavirus type 16 viral DNA in head and neck cancers. Cancer Prev Res 4:207–217

    Article  CAS  Google Scholar 

  • Patel DA, Rozek LS, Colacino JA, Zomeren-Dohm V, Ruffin M, Unger ER, Dolinoy DC, Swan DC, Onyekwuluje J, DeGraffinreid CR, Paskett ED (2012) Patterns of cellular and HPV16 methylation as biomarkers for cervical neoplasia. J Virol Methods 184:84–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peitsaro P, Johansson B, Syrjaenen S (2002) Integrated human papillomavirus type 16 is frequently found in cervical cancer precursors as demonstrated by a novel quantitative real-time PCR technique. J Clin Microbiol 40:886–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roman A, Munger K (2013) The papillomavirus E7 proteins. Virology 445:138–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rösl F, Arab A, Klevenz B, zur Hausen H (1993) The effect of DNA methylation on gene regulation of human papillomaviruses. J Gen Virol 74:791–801

    Article  PubMed  Google Scholar 

  • Sartor MA, Dolinoy DC, Jones TR, Colacino JA, Prince ME, Carey TE, Rozek LS (2011) Genome-wide methylation and expression differences in HPV(+) and HPV(−) squamous cell carcinoma cell lines are consistent with different mechanisms of carcinogenesis. Epigenetics 6:777–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saslow D, Solomon D, Lawson HW et al (2012) American cancer society, American society for colposcopy and cervical pathology, and American society for clinical pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol 137:516–542

    Article  PubMed  Google Scholar 

  • Schuebeler D (2015) Function and information content of DNA methylation. Nature 517:321–326

    Article  Google Scholar 

  • Schwarz E, Freese UK, Gissmann L, Mayer W, Roggenbuck B, Stremlau A, zur Hausen H (1985) Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 314:111–114

    Article  CAS  PubMed  Google Scholar 

  • Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36

    Article  CAS  PubMed  Google Scholar 

  • Siegel EM, Riggs BM, Delmas AL, Koch A, Hakam A, Brown KD (2015) Quantitative DNA methylation analysis of candidate genes in cervical cancer. PLoS One 10:e0122495

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith JA, Haberstroh FS, White EA, Livingston DM, DeCaprio JA, Howley PM (2014) SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter. Virology 470:311–321

    Article  Google Scholar 

  • Snellenberg S, Schütze DM, Claassen-Cramer D, Meijer C, Snijders PJ, Steenbergen RD (2012) Methylation status of the E2 binding sites of HPV16 in cervical lesions determined with the Luminex XMAP system. Virology 422:357–365

    Article  CAS  PubMed  Google Scholar 

  • Sugarawa K, Fujinaga K, Yamashita T, Ito Y (1983) Integration and methylation of shope papillomavirus DNA in the transplantable Vx2 and Vx7 rabbit carcinomas. Virology 130:88–99

    Article  Google Scholar 

  • Sun C, Reimers LL, Burk RD (2011) Methylation of HPV16 genome CpG sites is associated with cervix precancer and cancer. Gynecol Oncol 121:59–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan SH, Leong LEC, Walker PA, Bernard HU (1994) The human papillomavirus type 16 transcription factor E2 binds with low cooperativity to two flanking binding sites and represses the E6 promoter through displacement of Sp1 and TFIID. J Virol 68:6411–6420

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thain A, Jenkins O, Clarke AR, Gaston K (1996) CpG methylation directly inhibits binding of the human papillomavirus type 16 E2 protein to specific DNA sequences. J Virol 70:7233–7235

    CAS  PubMed  PubMed Central  Google Scholar 

  • Turan T, Kalantari M, Calleja-Macias IE, Villa LL, Cubie HA, Cuschieri K, Skomedal H, Barrera-Saldana HA, Bernard HU (2006) Methylation of the human papillomavirus-18 L1 gene: a biomarker of neoplastic progression? Virology 349:175–183

    Article  CAS  PubMed  Google Scholar 

  • Turan T, Kalantari M, Cuschieri K, Cubie HA, Skomedal H, Bernard HU (2007) High-throughput detection of human papillomavirus-18 L1 gene methylation, a candidate biomarker for the progression of cervical neoplasia. Virology 361:185–193

    Article  CAS  PubMed  Google Scholar 

  • Van Tine BA, Kappes JC, Banerjee NS, Knops J, Lai L, Steenbergen RD, Meijer CL, Snijders PJ, Chatis P, Broker TR, Moen PT Jr, Chow LT (2004) Clonal selection for transcriptionally active viral oncogenes during progression to cancer. J Virol 78:11172–11186

    Article  PubMed  PubMed Central  Google Scholar 

  • Vande Pol S, Klingelhutz AJ (2013) Papillomavirus E6 oncoproteins. Virology 445:115–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vasiljevic N, Scibior-Bentkowska D, Brentnall A, Cuzick J, Lorincz A (2014) A comparison of the methylation levels in HPV18, HPV31, and HPV33 genomes reveals similar associations with cervical precancers. J Clin Virol 59:161–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verhoef VM, Heideman DA, van Kemenade FJ, Rozendaal L, Bosgraaf RP, Hesselink AT, Bekkers RL, Massuger LF, Steenbergen RD, Snijders PJ, Berkhof J, Meijer CJ (2014) Methylation marker analysis and HPV16/18 genotyping in high-risk HPV positive self-sampled specimens to identify women with high grade CIN or cervical cancer. Gynecol Oncol 135:58–63

    Article  CAS  PubMed  Google Scholar 

  • Vinokurova S, von Knebel Doeberitz M (2011) Differential methylation of the HPV16 upstream regulatory region during epithelial differentiation and neoplastic transformation. PLoS One 6:e24451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang JW, Roden RBS (2013) L2, the minor capsid protein of papillomaviruses. Virology 445:175–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wentzensen N, Sherman ME, Schiffman M, Wang SS (2009) Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science. Gynecol Oncol 112:293–299

    Article  CAS  PubMed  Google Scholar 

  • Wentzensen N, Sun C, Ghosh A, Kinney W, Mirabello L, Wacholder S, Shaber R, LaMere B, Clarke M, Lorincz AT, Castle PE, Schiffman M, Burk RD (2012) Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3. J Natl Cancer Inst 104:1738–1749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wettstein FO, Stevens JG (1983) Shope papillomavirus DNA is extensively methylated in non-virus-producing neoplasms. Virology 126:493–504

    Article  CAS  PubMed  Google Scholar 

  • Wiley DJ, Huh J, Chang C, Kalantari M, Rao J, Goetz M, Msongsong E, Poulter M, Bernard HU (2005) Methylation of human papillomavirus DNA in samples of HIV-1 infected men screened for anal cancer. J Acqu Immunodef Syndr 39:143–151

    CAS  Google Scholar 

  • Xi LF, Jiang M, Shen Z, Hulbert A, Zhou XH, Lin YY, Kiviat NB, Koutsky LA (2011) Inverse association between methylation of human papillomavirus type 16 DNA and risk of cervical intraepithelial neoplasia grades 2 or 3. PLoS One 6:e23897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry and Program in Public Health, University of California Irvine, Irvine, CA, 92697, USA

    Hans-Ulrich Bernard

Authors
  1. Hans-Ulrich Bernard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans-Ulrich Bernard .

Editor information

Editors and Affiliations

  1. Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg Medical School, Erlangen, Bayern, Germany

    Walter Doerfler

  2. Departamento de Genética, Universidad de Sevilla, Sevilla, Spain

    Josep Casadesús

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Bernard, HU. (2017). DNA Methylation of Human Papillomavirus Genomes During Infection and Cancer Progression. In: Doerfler, W., Casadesús, J. (eds) Epigenetics of Infectious Diseases. Epigenetics and Human Health. Springer, Cham. https://doi.org/10.1007/978-3-319-55021-3_1

Download citation

Publish with us

Policies and ethics

Search

Navigation