Skip to main content
SpringerLink
Log in

Molecular Diagnosis and Monitoring of Human Papillomavirus Infections

  • Chapter
  • First Online:
Advanced Techniques in Diagnostic Microbiology

  • 1697 Accesses

Abstract

Cervical cancer screening algorithms are rapidly evolving with HPV DNA assays gaining regulatory approval for primary screening because of their well-documented high sensitivity. This makes clinical sense; however, issues remain because of the high clinical false positivity rate leading to unnecessary invasive follow-up procedures. Here, we present a comprehensive review of the technologies available in the market and the clinical utility with the ultimate goal being a screening program that balances high sensitivity and high specificity. Further, new therapies are being developed for women with pre-cervical cancer that may minimize the need for surgery. These new therapeutic approaches will also challenge the diagnostic approaches to stage the continuum of cervical carcinogenesis.

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
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

  1. ACS. Cancer facts and figures; 2009. American Cancer Society, Atlanta Georgia

    Google Scholar 

  2. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–9.

    Article  CAS  Google Scholar 

  3. Cox JT. History of the use of HPV testing in cervical screening and in the management of abnormal cervical screening results. J Clin Virol. 2009;45(Suppl 1):S3–S12.

    Article  Google Scholar 

  4. Schiffman M, Solomon D. Screening and prevention methods for cervical cancer. JAMA. 2009;302:1809–10.

    Article  CAS  Google Scholar 

  5. Cox JT. Human papillomavirus testing in primary cervical screening and abnormal Papanicolaou management. Obstet Gynecol Surv. 2006;61:S15–25.

    Article  Google Scholar 

  6. Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003;95:46–52.

    Article  Google Scholar 

  7. Reynolds J. HPV: a look into new methods for high-risk testing (2011). Med Lab Obs. 2011;43:10–2.

    Google Scholar 

  8. Wilbur DC, Facik MS, Rutkowski MA, Mulford DK, Atkison KM. Clinical trials of the CytoRich specimen-preparation device for cervical cytology. Preliminary results. Acta Cytol. 1997;41:24–9.

    Article  CAS  Google Scholar 

  9. Corkill M, Knapp D, Martin J, Hutchinson ML. Specimen adequacy of ThinPrep sample preparations in a direct-to-vial study. Acta Cytol. 1997;41:39–44.

    Article  CAS  Google Scholar 

  10. Tarkowski TA, Rajeevan MS, Lee DR, Unger ER. Improved detection of viral RNA isolated from liquid-based cytology samples. Mol Diagn. 2001;6:125–30.

    Article  CAS  Google Scholar 

  11. Zur Hausen HH. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2:342–50.

    Article  CAS  Google Scholar 

  12. Romanczuk H, Howley PM. Disruption of either the E1 or the E2 regulatory gene of human papillomavirus type 16 increases viral immortalization capacity. Proc Natl Acad Sci U S A. 1992;89:3159–63.

    Article  CAS  Google Scholar 

  13. McBride AA, Romanczuk H, Howley PM. The papillomavirus E2 regulatory proteins. J Biol Chem. 1991;266:18411–4.

    CAS  PubMed  Google Scholar 

  14. Munger KM, Scheffner M, Huibregtse JM, Howley PM. Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products. Cancer Surv. 1992;12:197–217.

    CAS  PubMed  Google Scholar 

  15. Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res. 2002;89:213–28.

    Article  CAS  Google Scholar 

  16. Cuscherieri K, Wentzensen N. HPV mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomark Prev. 2008;17:2536–45.

    Article  Google Scholar 

  17. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci. 2006;110:525–41.

    Article  CAS  Google Scholar 

  18. Kelly D, Kincaid E, Fansler Z, Rosenthal DL, Clark DP. Detection of cervical high grade squamous intraepithelial lesions from cytologic samples using a novel immunocy- tochemical assay (ProEx C). Cancer. 2006;108:494–500.

    Article  CAS  Google Scholar 

  19. Bedell MA, Jones KH, Laimins LA. The E6-E7 region of human papillomavirus type 18 is sufficient for transformation of NIH 3T3 and rat-1 cells. J Virol. 1987;61:3635–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Longworth MS, Wilson R, Laimins LA. HPV31 E7 facilitates replication by activating E2F2 transcription through its interaction with HDACs. EMBO J. 2005;24:1821–30.

    Article  CAS  Google Scholar 

  21. Howley PM, Scheffner M, Huibregtse J, Munger K. Oncoproteins encoded by the cancer-associated human papillomaviruses target the products of the retinoblastoma and p53 tumor suppressor genes. Cold Spring Harb Symp Quant Biol. 1991;56:149–55.

    Article  CAS  Google Scholar 

  22. Chellappan S, Kraus VB, Kroger B, et al. Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci U S A. 1992;89:4549–53.

    Article  CAS  Google Scholar 

  23. McIntyre MC, Ruesch MN, Laimins LA. Human papillomavirus E7 oncoproteins bind a single form of cyclin E in a complex with cdk2 and p107. Virology. 1996;215:73–82.

    Article  CAS  Google Scholar 

  24. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990;63:1129–36.

    Article  CAS  Google Scholar 

  25. Scheffner M, Munger K, Byrne JC, Howley PM. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A. 1991;88:5523–7.

    Article  CAS  Google Scholar 

  26. Scheffner M, Takahashi T, Huibregtse JM, Minna JD, Howley PM. Interaction of the human papillomavirus type 16 E6 oncoprotein with wild-type and mutant human p53 proteins. J Virol. 1992;66:5100–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Song S, Liem A, Miller JA, Lambert PM. Human papillomavirus types 16 E6 and E7 contribute differently to carcinogenesis. Virology. 2000;267:141–50.

    Article  CAS  Google Scholar 

  28. Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990;248:76–9.

    Article  CAS  Google Scholar 

  29. Sotlar K, Stubner A, Diemer D, et al. Detection of high-risk human papillomavirus E6 and E7 oncogene transcripts in cervical scrapes by nested RT-polymerase chain reaction. J Med Virol. 2004;74:107–16.

    Article  CAS  Google Scholar 

  30. Nakagawa S, Yoshikawa H, Yasugi T, et al. Ubiquitous presence of E6 and E7 transcripts in human papillomavirus-positive cervical carcinomas regardless of its type. J Med Virol. 2000;62:251–8.

    Article  CAS  Google Scholar 

  31. Stoler M, Schiffman M. Interobserver reproducibility of cervical cytologic and histo- logic interpretations: realistic estimates from the ASCUS-LSIL triage study. JAMA. 2001;285:1500–5.

    Article  CAS  Google Scholar 

  32. Szarewski A, Ambroisine L, Cadman L, et al. Comparison of predictors for high-grade cervical intraepithelial neoplasia in women with abnormal smears. Cancer Epidemiol Biomark Prev. 2008;17:3033–42.

    Article  CAS  Google Scholar 

  33. Kinney W, Stolar MH, Castle PE. Patient safety and the next generation of HPV DNA tests. Am J Clin Pathol. 2010;134:193–9.

    Article  Google Scholar 

  34. Wright TC Jr, Stolar MH, Sharma A, Zhang G, Behrens CM, Wright TL. Evaluation of HPV-16’and HPV-18 genotyping for the triage of HPV-positive cytology-negative women. Am J Clin Pathol. 2011;136:578–86.

    Article  Google Scholar 

  35. Stolar MH, Wright TC Jr, Sharma A, Apple R, Gutekunst K, Wright TL. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol. 2011;135:468–75.

    Article  Google Scholar 

  36. Narimatsu R, Patterson B. High throughput cervical cancer screening using intracellular HPV E6, E7 mRNA quantification by flow cytometry. Am J Clin Pathol. 2005;123:716–23.

    Article  Google Scholar 

  37. Coquillard G, Palao B, Patterson B. Quantification of intracellular HPV E6/E7 mRNA expression increases the specificity and positive predictive value of cervical cancer screening compared to HPV DNA. Gynecol Oncol. 2011;120:89–93.

    Article  CAS  Google Scholar 

  38. Pierry D, Lack B, Chen V, Fusco J, Weiss G. Intracellular HPV E6, E7 mRNA quantification (HPV Oncotect) predicts CIN 2+ in cervical biopsies better than pap screening for women regardless of age. Arch Pathol Lab Med. In press.

    Google Scholar 

  39. Tsoumpou I, Arbyn M, Kyrgiou M, Wentzensen N, Koliopoulos G, Martin-Hirsch P, Paraskevaidis E. p16INK4a immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev. 2009;35:210–20.

    Article  CAS  Google Scholar 

  40. Seppo A, RezaJalali G, et al. Gain of 3q26: a genetic marker in low-grade squamous intraepithelial lesions (LSIL) of the uterine cervix. Gynecol Oncol. 2009;114:80–3.

    Article  CAS  Google Scholar 

  41. Phanuphak P. Screening for anal intraepithelial neoplasia (AIN) using HPV Oncotect increases sensitivity and specificity compared to HPV DNA. Eurogin 2011, Lisbon, Portugal, 2011.

    Google Scholar 

  42. Vardas E, Giuliano AR, Goldstone S, et al. External genital human papillomavirus prevalence and associated factors among heterosexual men on 5 continents. J Infect Dis. 2011;203(1):58–65.

    Article  Google Scholar 

  43. Valari O, Koliopoulos G, Karakitsos P, et al. Human papillomavirus DNA and mRNA positivity of the anal canal in women with lower genital tract HPV lesions: predictors and clinical implications. Gynecol Oncol. 2011;122:505–8.

    Article  CAS  Google Scholar 

  44. Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol. 2006;24:5630–6.

    Article  CAS  Google Scholar 

  45. Reimers N, Kasper HU, Weissenborn SJ, et al. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer. 2007;120:1731–8.

    Article  CAS  Google Scholar 

  46. Klussmann JP, Gultekin E, Weissenborn SJ, et al. Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol. 2003;162:747–53.

    Article  CAS  Google Scholar 

  47. Ronco G, Giorgi-Rossi F, Carozzi F, et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test. J Natl Cancer Inst. 2008;100:492–501.

    Article  Google Scholar 

  48. Patterson BK, Lack B, Shults K. Combined nuclear-to-cytoplasmic ratio (N/C), E6, E7 mRNA Quantification, and DNA ploidy in suspension cervical cells. Eurogin 2011, Lisbon, Portugal, 2011.

    Google Scholar 

  49. Patterson BK, Chargin A. Biomarkers for staging of cervical precancerous lesions. Eurogin 2016, Salzburg, Austria, 2016.

    Google Scholar 

  50. Chargin A, Morgan R, Patterson BK. Combined single cell quantification of PD-L1 protein and HPV E6, E7 mRNA in head and neck cancer. ESMO 2017, Madrid, Spain, 2017.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. IncellDx, Inc, Menlo Park, CA, USA

    Bruce K. Patterson

Authors
  1. Bruce K. Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruce K. Patterson .

Editor information

Editors and Affiliations

  1. Departments of Laboratory Medicine and Internal Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Yi-Wei Tang

  2. Department of Pathology, Microbiology and Immunology and Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Charles W. Stratton

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Patterson, B.K. (2018). Molecular Diagnosis and Monitoring of Human Papillomavirus Infections. In: Tang, YW., Stratton, C. (eds) Advanced Techniques in Diagnostic Microbiology. Springer, Cham. https://doi.org/10.1007/978-3-319-95111-9_20

Download citation

Publish with us

Policies and ethics

Search

Navigation