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HPV Infection: Pathogenesis and Detection

  • Pakhee Aggarwal
Chapter

Abstract

Human papillomavirus (HPV) is one of the commonest sexually transmitted infections in the world. Over 150 types are known, of these, the ones with a predilection for humans are further divided into mucosal and cutaneous types. The former include the high-risk and low-risk HPV types. The high-risk types are linked to cervical, vaginal, vulvar, and anal cancer in women and penile, anal, and oropharyngeal cancer in men, while the low-risk types are responsible for warts and other benign pathologies in both sexes. Although HPV infection is easily acquired, most infections are subclinical and transient. Persistent HPV infection can predispose to cancer, which is mediated by the E6 and E7 oncogene products of the viral DNA. Integration of the HPV genome with the host genome is a crucial event in this cycle of carcinogenesis. Detection relies on molecular methods, as HPV cannot be grown in culture. Several tests are available, based on two principal techniques—hybrid capture and PCR. In general, there is good correlation between the two, although the former is more suited to detecting HPV as high risk or low risk, the latter is more accurate for genotyping. Both are amenable to automation and high-throughput testing. Five tests between the two are US FDA approved for detecting HPV infection.

Keywords

HPV infection Molecular methods High-risk HPV E6/E7 mRNA Genotyping 

References

  1. 1.
    de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324:17–27.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Bonnez W, Reichman RC. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. Philadelphia: Churchill Livingstone; 2000. p. 1630–44.Google Scholar
  3. 3.
    Zur Hausen H. Papillomavirus infections-a major cause of human cancers. Biochem Biophys Acta. 1996;1288:F55–78.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. J Natl Cancer Inst. 2015;107(6):djv086.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bosch FX, de Sanjosé S. The epidemiology of human papillomavirus infection and cervical cancer. Dis Markers. 2007;23(4):213–27.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    de Sanjosé S, Diaz M, Castellsagué X, Clifford G, Bruni L, Muñoz N, et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. 2007;7(7):453–9.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Gómez DT, Santos JL. Human papillomavirus infection and cervical cancer: pathogenesis and epidemiology. In: Méndez-Vilas A, editor. Communicating current research and educational topics and trends in applied microbiology: Formatex. p. 660–8.Google Scholar
  8. 8.
    Herfs M, Hubert P, Moutschen M, Delvenne P. Mucosal junctions: open doors to HPV and HIV infections? Trends Microbiol. 2011;19(3):114–20.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Fernandes JV, Fernandes TAA. In: Broeck DV, editor. Human papillomavirus: biology and pathogenesis, human papillomavirus and related diseases—from bench to bedside—a clinical perspective. London: Intech; 2012. p. 1–39.Google Scholar
  10. 10.
    Watt FM. Epidermal stem cells: markers, patterning and the control of stem cell fate. Philos Trans R Soc Lond Ser B Biol Sci. 1998;353:831–7.CrossRefGoogle Scholar
  11. 11.
    Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005;32(S1):S7–15.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Ebisch RM, Siebers AG, Bosgraaf RP, Massuger LF, Bekkers RL, Melchers WJ. Triage of high-risk HPV positive women in cervical cancer screening. Expert Rev Anticancer Ther. 2016;16(10):1073–85.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Yoshinouchi M, Hongo A, Nakamura K, Kodoma J, Itoh S, Sakai H, et al. Analysis by multiplex PCR of the physical status of human papillomavirus type 16 DNA in cervical cancers. J Clin Microbiol. 1999;37(11):3514–7.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Doorbar J, Egawa N, Griffin H, Kranjec C, Murakami I. Human papillomavirus molecular biology and disease association. Rev Med Virol. 2015;25(Suppl 1):2–23.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338:423–8.CrossRefGoogle Scholar
  16. 16.
    Rodriguez AC, Schiffman M, Herrero R, Wacholder S, Hildesheim A, Castle PE, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst. 2008;100(7):513–7.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol. 2005;32(Suppl 1):S16–24.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    von Knebel Doeberitz M. New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur J Cancer. 2002;38:2229–42.CrossRefGoogle Scholar
  19. 19.
    Vinokurova S, Wentzensen N, Kraus I, Klaes R, Driesch C, Melsheimer P, et al. Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res. 2008;68:307–13.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Doorbar J, Foo C, Coleman N, Medcalf L, Hartley O, Prospero T, et al. Characterization of events during the late stages of HPV16 infection in vivo using high-affinity synthetic Fabs to E4. Virology. 1997;238(1):40–52.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Stanley MA. Immune responses to human papilloma viruses. Indian J Med Res. 2009;130(3):266–76.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol. 2007;212:356–67.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Mantovani F, Banks L. The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene. 2001;20:7874–87.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Grm HS, Bergant M, Banks L. Human papillomavirus infection, cancer & therapy. Indian J Med Res. 2009;130(3):277–85.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Howie HL, Katzenellenbogen RA, Galloway DA. Papillomavirus E6 proteins. Virology. 2009;384(2):324–34.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Pang CL, Thierry F. Human papillomavirus proteins as prospective therapeutic targets. Microb Pathog. 2013;58:55–65.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007;7(4):233–45.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Bodily JM, Mehta KP, Laimins LA. Human papillomavirus E7 enhances hypoxia-inducible factor 1-mediated transcription by inhibiting binding of histone deacetylases. Cancer Res. 2011;71(3):1187–95.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Arbyn M, Anttila A, Jordan J, Ronco G, Schenck U, Segnan N, et al. European guidelines for quality assurance in cervical cancer screening. Second edition-summary document. Ann Oncol. 2010;21(3):448–58.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Gao P, Zheng J. High-risk HPV E5-induced cell fusion: a critical initiating event in the early stage of HPV-associated cervical cancer. Virol J. 2010;7:238.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Alcocer-Gonzalez JM, Berumen J, Tamez-Guerra R, Bermudez-Morales V, Peralta-Zaragoza O, Hernandez-Pando R, et al. In vivo expression of immunosuppressive cytokines in human papillomavirus—transformed cervical cancer cells. Viral Immunol. 2006;19(3):481–91.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    van der Burg SH, Palefsky JM. Human immunodeficiency virus and human papilloma virus—why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful. J Transl Med. 2009;7:108.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Insinga RP, Perez G, Wheeler CM, Koutsky LA, Garland SM, Leodolter S, et al. Incidence, duration, and reappearance of type-specific cervical human papillomavirus infections in young women. Cancer Epidemiol Biomark Prev. 2010;19(6):1585–94.CrossRefGoogle Scholar
  34. 34.
    Muñoz N, Bosch FX, Castellsagué X, Díaz M, de Sanjose S, Hammouda D, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer. 2004;111(2):278–85.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Bulk S, Berkhof J, Bulkmans NW, Zielinski GD, Rozendaal L, van Kemenade FJ, et al. Preferential risk of HPV16 for squamous cell carcinoma and of HPV18 for adenocarcinoma of the cervix compared to women with normal cytology in The Netherlands. Br J Cancer. 2006;94(1):171–5.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Levi JE, Kleter B, Quint WG, Fink MC, Canto CL, Matsubara R, et al. High prevalence of human papillomavirus (HPV) infections and high frequency of multiple HPV genotypes in human immunodeficiency virus-infected women in Brazil. J Clin Microbiol. 2002;40(9):3341–5.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Brink AATP, Snijders PJF, Meijer CJLM. HPV detection methods. Dis Markers. 2007;23:273–81.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Zaravinos A, Mammas IN, Sourvinos G, Spandidos DA. Molecular detection methods of human papillomavirus (HPV). Int J Biol Markers. 2009;24(4):215–22.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Villa LL. Human papillomavirus. In: Rosenblatt A, Guidi HGC, editors. Laboratory methods for detection of human papillomavirus infection. Berlin: Springer; 2009. p. 23–30.Google Scholar
  40. 40.
    Nuovo GJ, Moritz J, Walsh LL, MacConnell P, Koulos J. Predictive value of human papillomavirus DNA detection by filter hybridization and polymerase chain reaction in women with negative results of colposcopic examination. Am J Clin Pathol. 1992;98(5):489–92.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Stoler MH, Wolinsky SM, Whitbeck A, Broker TR, Chow LT. Differentiation-linked human papillomavirus types 6 and 11 transcription in genital condylomata revealed by in situ hybridization with message-specific RNA probes. Virology. 1989;172(1):331–40.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Ylitalo N, Sorensen P, Josefsson AM, Magnusson PK, Andersen PK, Pontén J, et al. Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study. Lancet. 2000;355(9222):2194–8.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Lorincz A, Anthony J. Advances in HPV detection by hybrid capture. Papillomavirus Rep. 2001;12:145–54.Google Scholar
  44. 44.
    Abreu AL, Souza RP, Gimenes F, Consolaro ME. A review of methods for detect human papillomavirus infection. Virol J. 2012;9:262.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Qiao YL, Sellors JW, Eder PS, Bao YP, Lim JM, Zhao FH, et al. A new HPV-DNA test for cervical cancer screening in developing regions: a cross sectional study of clinical accuracy in rural China. Lancet Oncol. 2008;9(10):926–36.CrossRefGoogle Scholar
  46. 46.
    Piana A, Sotgiu G, Castiglia P, Pischedda S, Dettori M, Cocuzza C, et al. Molecular methods for the detection of human papillomavirus infection: new insights into their role in diagnostics and epidemiological surveillance. JPH. 2009;7(6):164–71.Google Scholar
  47. 47.
    Einstein MH, Martens MG, Garcia FA, Ferris DG, Mitchell AL, Day SP, et al. Clinical validation of the Cervista HPV HR and 16/18 genotyping tests for use in women with ASC-US cytology. Gynecol Oncol. 2010;118:116–22.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Tieben LM, ter Schegget J, Minnaar RP, Bouwes Bavinck JN, Berkhout RJ, Vermeer BJ, et al. Detection of cutaneous and genital HPV types in clinical samples by PCR using consensus primers. J Virol Methods. 1993;42:265–79.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Carvalho NO, del Castillo DM, Perone C, Januário JN, Melo VH, Brasileiro FG. Comparison of HPV genotyping by type-specific PCR and sequencing. Mem Inst Oswaldo Cruz. 2010;105:73–8.CrossRefGoogle Scholar
  50. 50.
    Gravitt PE, Peyton CL, Alessi TQ, Wheeler CM, Coutlée F, Hildesheim A, et al. Improved amplification of genital human papillomaviruses. J Clin Microbiol. 2000;38(1):357–61.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Peyton CL, Schiffman MA, Lorincz AT, Hunt WC, Mielzynska I, Bratti C, et al. Comparison of PCR and hybrid capture-based human papillomavirus detection system using multiple cervical specimen collection strategies. J Clin Microbiol. 1998;36:3248–54.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Kado S, Kawamata Y, Shino Y, Kasai T, Kubota K, Iwasaki H, et al. Detection of human papillomaviruses in cervical neoplasias using multiple sets of generic polymerase chain reaction primers. Gynecol Oncol. 2001;81(1):47–52.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Grce M, Husnjak K, Skerlev M, Lipozencić J, Pavelić K. Detection and typing of human papillomaviruses by means of polymerase chain reaction and fragment length polymorphism in male genital lesions. Anticancer Res. 2000;20:2097–102.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Kim CJ, Jeong JK, Park M, Park TS, Park TC, Namkoong SE, et al. HPV oligonucleotide microarray-based detection of HPV genotypes in cervical neoplastic lesions. Gynecol Oncol. 2003;89:210–7.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Brandstetter T, Böhmer S, Prucker O, Bissé E, zur Hausen A, Alt-Mörbe J, et al. A polymerase based DNA biochip platform for human papillomavirus genotyping. J Virol Methods. 2010;163:40–8.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Coser J, Boeira TR, Fonseca AS, Ikuta N, Lunge VR. Human papillomavirus detection and typing using a nested-PCR-RFLP assay. Braz J Infect Dis. 2011;15:467–72.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Iftner T, Villa LL. Human papillomavirus technologies. J Natl Cancer Inst Monogr. 2003;31:80–8.CrossRefGoogle Scholar
  58. 58.
    Szarewski A, Ambroisine L, Cadman L, Austin J, Ho L, Terry G, et al. Comparison of predictors for high-grade cervical intraepithelial neoplasia in women with abnormal smears. Cancer Epidemiol Biomark Prev. 2008;17:3033–42.CrossRefGoogle Scholar
  59. 59.
    Hoheisel JD. Microarray technology: beyond transcript profiling and genotype analysis. Nat Rev Genet. 2006;7:200–10.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Didelot MN, Boulle N, Damay A, Costes V, Segondy M. Comparison of the PapilloCheck assay with the digene HC2 HPV DNA assay for the detection of 13 high-risk human papillomaviruses in cervical and anal scrapes. J Med Virol. 2011;83:1377–82.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Dalstein V, Merlin S, Bali C, Saunier M, Dachez R, Ronsin C. Analytical evaluation of the PapilloCheck test, a new commercial DNA chip for detection and genotyping of papillomavirus. J Virol Methods. 2009;156:77–83.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Otero-Motta AP, Ordóñez JL, González-Celador R, Rivas B, Macías M, Macías MC, et al. Prevalence of human papillomavirus genotypes in cytologic abnormalities from unvaccinated women living in North-Western Spain. APMIS. 2011;119:204–15.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Kocjan BJ, Seme K, Poljak M. Comparison of the Abbott real time high risk HPV test and INNO-LiPA HPV genotyping extra test for the detection of human papillomaviruses in formalin-fixed, paraffin- embedded cervical cancer specimens. J Virol Methods. 2011;175:117–9.PubMedCrossRefGoogle Scholar
  64. 64.
    van Hamont D, van Ham MA, Bakkers JM, Massuger LF, Melchers WJ. Evaluation of the SPF10-Inno LiPA human papillomavirus (HPV) genotyping test and the roche linear array HPV genotyping test. J Clin Microbiol. 2006;44:3122–9.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Dobec M, Bannwart F, Kilgus S, Kaeppeli F, Cassinotti P. Human papillomavirus infection among women with cytological abnormalities in Switzerland investigated by an automated linear array genotyping test. J Med Virol. 2011;83:1370–6.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Schmitt M, Bravo IG, Snijders PJ, Gissmann L, Pawlita M, Waterboer T. Bead-based multiplex genotyping of human papillomaviruses. J Clin Microbiol. 2006;44:504–12.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Barcellos RB, Almeida SE, Sperhacke RD, Verza M, Rosso F, Medeiros RM, et al. Evaluation of a novel microplate colorimetric hybridization genotyping assay for human papillomavirus. J Virol Methods. 2011;177:38–43.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Roberts I, Ng G, Foster N, Stanley M, Herdman MT, Pett MR, et al. Critical evaluation of HPV16 gene copy number quantification by SYBR green PCR. BMC Biotechnol. 2008;8:57.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Halfon P, Benmoura D, Agostini A, Khiri H, Penaranda G, Martineau A, et al. Evaluation of the clinical performance of the Abbott RealTime high-risk HPV for carcinogenic HPV detection. J Clin Virol. 2010;48(4):246–50.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Heideman DA, Hesselink AT, Berkhof J, van Kemenade F, Melchers WJ, Daalmeijer NF, et al. Clinical validation of the Cobas 4800 HPV test for cervical screening purposes. J Clin Microbiol. 2011;49:3983–5.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Mateos ML, Rodríguez-Domínguez M, Sanz I, Rubio MD, Antonio J, Chacón D. Evaluation of a prototype real-time PCR assay for the separate detection of human papillomavirus genotypes 16 and 18 and other high risk human papillomavirus in cervical cancer screening. Enferm Infecc Microbiol Clin. 2011;29:411–4.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    de Araujo MR, De Marco L, Santos CF, Rubira-Bullen IR, Ronco G, Pennini I, et al. GP5+/6+ SYBR green methodology for simultaneous screening and quantification of human papillomavirus. J Clin Virol. 2009;45:90–5.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Biotechnology. 1992;24:104–8.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Novais RC, Thorstenson YR. The evolution of pyrosequencing for microbiology: from genes to genomes. J Microbiol Methods. 2011;86:1–7.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Pista A, Verdasca N, Oliveira A. Clinical performance of the CLART human papillomavirus 2 assay compared with the hybrid capture 2 test. J Med Virol. 2011;83:272–6.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Wentzensen N, von Knebel DM. Biomarkers in cervical cancer screening. Dis Markers. 2007;23:315–30.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Hwang SJ, Shroyer KR. Biomarkers of cervical dysplasia and carcinoma. J Oncol. 2012;2012:507286.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Varnai AD, Bollmann M, Bankfalvi A, Speich N, Schmitt C, Griefingholt H, et al. Predictive testing of early cervical pre-cancer by detecting human papillomavirus E6/E7 mRNA in cervical cytologies up to high-grade squamous intraepithelial lesions: diagnostic and prognostic implications. Oncol Rep. 2008;19(2):457–65.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Dockter J, Schroder A, Eaton B, Wang A, Sikhamsay N, Morales L, et al. Analytical characterization of the APTIMA HPV assay. J Clin Virol. 2009;45(Suppl 1):39–47.CrossRefGoogle Scholar
  80. 80.
    Molden T, Kraus I, Karlsen F, Skomedal H, Nygård JF, Hagmar B. Comparison of human papillomavirus messenger RNA and DNA detection: a cross-sectional study of 4,136 women >30 years of age with a 2-year follow-up of high-grade squamous intraepithelial lesion. Cancer Epidemiol Biomark Prev. 2005;14(2):367–72.CrossRefGoogle Scholar
  81. 81.
    Cuschieri KS, Whitley MJ, Cubie H. Human papillomavirus type specific DNA and RNA persistence—implications for cervical disease progression and monitoring. J Med Virol. 2004;73:65–70.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Lowe B, O’Neil D, Loeffert D, Nazarenko I. Distribution of human papillomavirus load in clinical specimens. J Virol Methods. 2011;173:150–2.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Gravitt PE, Kovacic MB, Herrero R, Schiffman M, Bratti C, Hildesheim A, et al. High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts development incident disease. Int J Cancer. 2007;21:2787–93.CrossRefGoogle Scholar
  84. 84.
    Broccolo F, Chiari S, Piana A, Castiglia P, Dell’Anna T, Garcia-Parra R, et al. Prevalence and viral load of oncogenic human papillomavirus types associated with cervical carcinoma in a population of North Italy. J Med Virol. 2009;81:278–87.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Hart KW, Williams OM, Thelwell N, Fiander AN, Brown T, Borysiewicz LK, et al. Novel method for detection, typing, and quantification of human papillomaviruses in clinical samples. J Clin Microbiol. 2001;39:3402–12.CrossRefGoogle Scholar
  86. 86.
    Kulmala SM, Syrjänen SM, Gyllensten UB, Shabalova IP, Petrovichev N, Tosi P, et al. Early integration of high copy HPV16 detectable in women with normal and low grade cervical cytology and histology. J Clin Pathol. 2006;59:513–7.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Gallo G, Bibbo M, Bagella L, Zamparelli A, Sanseverino F, Giovagnoli MR, et al. Study of viral integration of HPV-16 in young patients with LSIL. J Clin Pathol. 2003;56:532–6.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Yoshida T, Sano T, Kanuma T, Owada N, Sakurai S, Fukuda T, et al. Quantitative real-time polymerase chain reaction analysis of the type distribution, viral load, and physical status of human papillomavirus in liquid-based cytology samples from cervical lesions. Int J Gynecol Cancer. 2008;18:121–7.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Jin Y, Li JP, He D, Tang LY, Zee CS, Guo SZ, et al. Clinical significance of human telomerase RNA gene (hTERC) amplification in cervical squamous cell lesions detected by fluorescence in situ hybridization. Asian Pac J Cancer Prev. 2011;12:1167–71.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, et al. hEST2, the putative human telomerase catalytic subunit gene, is upregulated in tumor cells and during immortalization. Cell. 1997;90:785–95.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Liu X, Yuan H, Fu B, Disbrow GL, Apolinario T, Tomaic V, et al. The E6AP ubiquitin ligase is required for transactivation of the hTERT promoter by the human papillomavirus E6 oncoprotein. J Biol Chem. 2005;280:10807–16.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Matovina M, Sabol I, Grubisić G, Gasperov NM, Grce M. Identification of human papillomavirus type 16 integration sites in high-grade precancerous cervical lesions. Gynecol Oncol. 2009;113:120–7.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Klaes R, Woerner SM, Ridder R, Wentzensen N, Duerst M, Schneider A, 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):6312–6.Google Scholar
  94. 94.
    Nonogaki S, Wakamatsu A, Longatto Filho A, Pereira SM, Utagawa ML, Ferreira Alves VA, et al. Hybrid capture II and polymerase chain reaction for identifying HPV infections in samples collected in a new collection medium. A comparison. Acta Cytol. 2004;48(4):514–20.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Choo KB, Pan CC, Han SH. Integration of human papillomavirus type 16 into cellular DNA of cervical carcinoma: preferential deletion of the E2 gene and invariable retention of the long control region and the E6/E7 open reading frames. Virology. 1987;161:259–61.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Rabelo-Santos SH, Levi JE, Derchain SF, Sarian LO, Zeferino LC, Messias S, et al. DNA recovery from hybrid capture II samples stored in specimen transport medium with denaturing reagent, for the detection of human papillomavirus by PCR. J Virol Methods. 2005;126(1–2):197–201.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Snijders PJ, van den Brule AJ, Meijer CJ. The clinical relevance of human papillomavirus testing: relationship between analytical and clinical sensitivity. J Pathol. 2003;201(1):1–6.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Villa LL, Denny L. Methods for detection of HPV infection and its clinical utility. Int J Gynaecol Obstet. 2006;94(Suppl 1):S71–80.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Pakhee Aggarwal
    • 1
  1. 1.Department of Obstetrics and GynaecologyFortis Memorial Research InstituteGurugramIndia

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