Carcinogenic human papillomavirus infection

Abstract

Infections with human papillomavirus (HPV) are common and transmitted by direct contact. Although the great majority of infections resolve within 2 years, 13 phylogenetically related, sexually transmitted HPV genotypes, notably HPV16, cause — if not controlled immunologically or by screening — virtually all cervical cancers worldwide, a large fraction of other anogenital cancers and an increasing proportion of oropharyngeal cancers. The carcinogenicity of these HPV types results primarily from the activity of the oncoproteins E6 and E7, which impair growth regulatory pathways. Persistent high-risk HPVs can transition from a productive (virion-producing) to an abortive or transforming infection, after which cancer can result after typically slow accumulation of host genetic mutations. However, which precancerous lesions progress and which do not is unclear; the majority of screening-detected precancers are treated, leading to overtreatment. The discovery of HPV as a carcinogen led to the development of effective preventive vaccines and sensitive HPV DNA and RNA tests. Together, vaccination programmes (the ultimate long-term preventive strategy) and screening using HPV tests could dramatically alter the landscape of HPV-related cancers. HPV testing will probably replace cytology-based cervical screening owing to greater reassurance when the test is negative. However, the effective implementation of HPV vaccination and screening globally remains a challenge.

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Figure 1: Conceptual model of HPV infection leading to cervical cancer.
Figure 2: Global burden of HPV-attributable cancer in 2012.
Figure 3: Factors that influence the age-specific HPV prevalence in women.
Figure 4: HPV structure and genome organization.
Figure 5: HPV infection and the transformation zone.
Figure 6: Molecular events during progression and invasion in the cervix.
Figure 7: Cervical screening strategies in high-resource and low-resource settings.

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Acknowledgements

J.D. is supported by the UK Medical Research Council through programme grant MC_U117584278 (Molecular Biology of Human Papillomavirus Infection).

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Introduction (M.S.); Epidemiology (S.d.S., S.F., M.S. and N.W.); Mechanisms/pathophysiology (J.D. and M.A.S.); Diagnosis, screening and prevention (N.W., M.A.S., S.F. and M.S.); Management (B.J.M. and C.F.); Quality of life (M.S.); Outlook (all authors); Overview of the Primer (M.S.). All authors were involved in the editing of the manuscript.

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Correspondence to Mark Schiffman.

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Competing interests

M.A.S. has served as a consultant for Sanofi Pasteur MSD, GSK Biologicals and Merck Vaccines. S.d.S. has received institutional grants from Merck for research and educational projects and has conducted trials of vaccine products developed by Genticel and Merck. M.S. and N.W. have conducted US National Cancer Institute-led projects on HPV testing and cytology interpretations at reduced or no cost with BD Biosciences, Roche and Qiagen. J.D., C.F., B.J.M. and S.F. declare no competing interests.

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Schiffman, M., Doorbar, J., Wentzensen, N. et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2, 16086 (2016). https://doi.org/10.1038/nrdp.2016.86

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