Virology of human papillomavirus infections and the link to cancer
- Joel M Palefsky, MD
Joel M Palefsky, MD
- University of California San Francisco
- Immediate Past President, International Papillomavirus Society
- Immediate Past President, International Anal Neoplasia Society
- Ross D Cranston, MD
Ross D Cranston, MD
- Visiting Professor
- Fundació Lluita contra la Sida
- Hospital Universitari Germans Trias i Pujol
- Autonomous University of Barcelona
- Barcelona, Spain
- Section Editors
- Don S Dizon, MD, FACP
Don S Dizon, MD, FACP
- Section Editor – Gynecologic Oncology
- Clinical Co-Director, Gynecologic Oncology
- Founder and Director, The Oncology Sexual Health Clinic
- Massachusetts General Hospital Cancer Center
- Associate Professor of Medicine
- Harvard Medical School
- David M Aboulafia, MD
David M Aboulafia, MD
- Section Editor — AIDS-Related Malignancies
- Section Head
- Division of Hematology and Oncology
- Virginia Mason Medical Center
- Clinical Professor
Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. The biology of these viruses has been studied extensively and its link with malignancies is well established, specifically with cancers involving the anogenital (cervical, vaginal, vulvar, penile, anal) tract and those involving the head and neck. The virology of HPV and its association with malignancy will be reviewed here. The clinical manifestations, diagnosis, epidemiology, prevention, and treatment of HPV infection are discussed separately. (See "Human papillomavirus infections: Epidemiology and disease associations".)
Human papillomavirus (HPV) is a small deoxyribonucleic acid (DNA) virus of approximately 7900 base pairs. DNA sequencing techniques have facilitated HPV typing and characterization, with each type formally defined as distinct by having less than 90 percent DNA base-pair homology with any another HPV type . There are over 40 HPV types that infect the anogenital area.
HPV GENOTYPES AND RISK OF CANCER
There are numerous human papillomavirus (HPV) genotypes, and their association with cancer risk varies. This is reviewed below.
Cervical cancer — There is a broad separation of HPV genotypes based on their associated risk of cervical cancer:
●High-risk – This includes HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
- Tilston P. Anal human papillomavirus and anal cancer. J Clin Pathol 1997; 50:625.
- de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11:1048.
- Hildesheim A, Schiffman M, Bromley C, et al. Human papillomavirus type 16 variants and risk of cervical cancer. J Natl Cancer Inst 2001; 93:315.
- Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000; 92:709.
- Beachler DC, DʼSouza G. Oral human papillomavirus infection and head and neck cancers in HIV-infected individuals. Curr Opin Oncol 2013; 25:503.
- D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007; 356:1944.
- Beachler DC, Weber KM, Margolick JB, et al. Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults. Cancer Epidemiol Biomarkers Prev 2012; 21:122.
- Palefsky JM, Holly EA, Ralston ML, Jay N. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis 1998; 177:361.
- Bosch FX, Manos MM, Muñoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995; 87:796.
- Zaki SR, Judd R, Coffield LM, et al. Human papillomavirus infection and anal carcinoma. Retrospective analysis by in situ hybridization and the polymerase chain reaction. Am J Pathol 1992; 140:1345.
- Frisch M, Glimelius B, van den Brule AJ, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med 1997; 337:1350.
- Maden C, Sherman KJ, Beckmann AM, et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst 1993; 85:19.
- Varma VA, Sanchez-Lanier M, Unger ER, et al. Association of human papillomavirus with penile carcinoma: a study using polymerase chain reaction and in situ hybridization. Hum Pathol 1991; 22:908.
- zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000; 92:690.
- Palefsky JM, Holly EA. Molecular virology and epidemiology of human papillomavirus and cervical cancer. Cancer Epidemiol Biomarkers Prev 1995; 4:415.
- Palefsky JM. Anal human papillomavirus infection and anal cancer in HIV-positive individuals: an emerging problem. AIDS 1994; 8:283.
- Münger K, Phelps WC, Bubb V, et al. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 1989; 63:4417.
- Vogelstein B, Fearon ER, Kern SE, et al. Allelotype of colorectal carcinomas. Science 1989; 244:207.
- Masuda H, Miller C, Koeffler HP, et al. Rearrangement of the p53 gene in human osteogenic sarcomas. Proc Natl Acad Sci U S A 1987; 84:7716.
- Hinds P, Finlay C, Levine AJ. Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J Virol 1989; 63:739.
- Dupuy C, Buzoni-Gatel D, Touze A, et al. Cell mediated immunity induced in mice by HPV 16 L1 virus-like particles. Microb Pathog 1997; 22:219.
- Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993; 75:495.
- Havre PA, Yuan J, Hedrick L, et al. p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. Cancer Res 1995; 55:4420.
- Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 1990; 248:76.
- Oda H, Kumar S, Howley PM. Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination. Proc Natl Acad Sci U S A 1999; 96:9557.
- Puthenveettil JA, Frederickson SM, Reznikoff CA. Apoptosis in human papillomavirus16 E7-, but not E6-immortalized human uroepithelial cells. Oncogene 1996; 13:1123.
- Magal SS, Jackman A, Pei XF, et al. Induction of apoptosis in human keratinocytes containing mutated p53 alleles and its inhibition by both the E6 and E7 oncoproteins. Int J Cancer 1998; 75:96.
- Pagano M, Dürst M, Joswig S, et al. Binding of the human E2F transcription factor to the retinoblastoma protein but not to cyclin A is abolished in HPV-16-immortalized cells. Oncogene 1992; 7:1681.
- Schwarz E, Freese UK, Gissmann L, et al. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 1985; 314:111.
- Tommasino M, Adamczewski JP, Carlotti F, et al. HPV16 E7 protein associates with the protein kinase p33CDK2 and cyclin A. Oncogene 1993; 8:195.
- Demers GW, Foster SA, Halbert CL, Galloway DA. Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. Proc Natl Acad Sci U S A 1994; 91:4382.
- Brehm A, Nielsen SJ, Miska EA, et al. The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J 1999; 18:2449.
- Antinore MJ, Birrer MJ, Patel D, et al. The human papillomavirus type 16 E7 gene product interacts with and trans-activates the AP1 family of transcription factors. EMBO J 1996; 15:1950.
- Massimi P, Pim D, Banks L. Human papillomavirus type 16 E7 binds to the conserved carboxy-terminal region of the TATA box binding protein and this contributes to E7 transforming activity. J Gen Virol 1997; 78 ( Pt 10):2607.
- Jones DL, Alani RM, Münger K. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev 1997; 11:2101.
- Zerfass-Thome K, Zwerschke W, Mannhardt B, et al. Inactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein. Oncogene 1996; 13:2323.
- Francis DA, Schmid SI, Howley PM. Repression of the integrated papillomavirus E6/E7 promoter is required for growth suppression of cervical cancer cells. J Virol 2000; 74:2679.
- Conley LJ, Ellerbrock TV, Bush TJ, et al. HIV-1 infection and risk of vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia: a prospective cohort study. Lancet 2002; 359:108.
- Vernon SD, Hart CE, Reeves WC, Icenogle JP. The HIV-1 tat protein enhances E2-dependent human papillomavirus 16 transcription. Virus Res 1993; 27:133.
- Chen Z, Kamath P, Zhang S, et al. Effectiveness of three ribozymes for cleavage of an RNA transcript from human papillomavirus type 18. Cancer Gene Ther 1995; 2:263.
- Bartsch D, Boye B, Baust C, et al. Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor beta gene in non-tumorigenic and tumorigenic HeLa hybrid cells. EMBO J 1992; 11:2283.
- Braun L, Dürst M, Mikumo R, Gruppuso P. Differential response of nontumorigenic and tumorigenic human papillomavirus type 16-positive epithelial cells to transforming growth factor beta 1. Cancer Res 1990; 50:7324.
- Woodworth CD, Notario V, DiPaolo JA. Transforming growth factors beta 1 and 2 transcriptionally regulate human papillomavirus (HPV) type 16 early gene expression in HPV-immortalized human genital epithelial cells. J Virol 1990; 64:4767.
- Khan MA, Tolleson WH, Gangemi JD, Pirisi L. Inhibition of growth, transformation, and expression of human papillomavirus type 16 E7 in human keratinocytes by alpha interferons. J Virol 1993; 67:3396.
- Soto U, Das BC, Lengert M, et al. Conversion of HPV 18 positive non-tumorigenic HeLa-fibroblast hybrids to invasive growth involves loss of TNF-alpha mediated repression of viral transcription and modification of the AP-1 transcription complex. Oncogene 1999; 18:3187.
- Storey A, Thomas M, Kalita A, et al. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 1998; 393:229.
- Chen TM, Pecoraro G, Defendi V. Genetic analysis of in vitro progression of human papillomavirus-transfected human cervical cells. Cancer Res 1993; 53:1167.
- Palefsky JM. Cutaneous and genital HPV-associated lesions in HIV-infected patients. Clin Dermatol 1997; 15:439.
- Schiffman M, Wentzensen N, Wacholder S, et al. Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst 2011; 103:368.
- Ikenberg H, Bergeron C, Schmidt D, et al. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study. J Natl Cancer Inst 2013; 105:1550.
- HPV GENOTYPES AND RISK OF CANCER
- Cervical cancer
- Head and neck cancer
- Anal cancer
- Penile cancer
- MOLECULAR PATHOGENESIS
- HPV proteins
- Role of p53 protein
- Role of retinoblastoma protein
- Other proteins
- HIV infection
- Progression from immortalization to malignancy
- RISK FACTORS FOR HPV INFECTION
- DETECTING HPV
- Indications for testing
- INFORMATION FOR PATIENTS