Human papillomaviruses are small DNA viruses that cause hyperproliferative lesions of the mucosa and skin. Some HPV types, collectively known as high-risk types, are etiologically associated to cervical cancer and other anogenital malignancies. Infection by these HPV types has been associated to genomic instability, a hallmark of most human malignancies. High-risk HPV types express two oncoproteins, E6 and E7, which target specific cellular factors to promote cell proliferation. Furthermore, these proteins induce structural and numerical chromosome alterations and modulate cellular response to DNA damage. These observations are discussed in the context of cervical carcinogenesis.

1.
Alazawi W, Pett M, Strauss S, Moseley R, Gray J, Stanley M, Coleman N: Genomic imbalances in 70 snap-frozen cervical squamous intraepithelial lesions: associations with lesion grade, state of the HPV16 E2 gene and clinical outcome. Br J Cancer 91:2063–2070 (2004).
2.
Arias-Pulido H, Narayan G, Vargas H, Mansukhani M, Murty VV: Mapping common deleted regions on 5p15 in cervical carcinoma and their occurrence in precancerous lesions. Mol Cancer 1:3 (2002).
3.
Baker CC, Phelps WC, Lindgren V, Braun MJ, Gonda MA, Howley PM: Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines. J Virol 61:962–971 (1987).
4.
Banerjee NS, Genovese NJ, Noya F, Chien WM, Broker TR, Chow LT: Conditionally activated E7 proteins of high-risk and low-risk human papillomaviruses induce S phase in postmitotic, differentiated human keratinocytes. J Virol 80:6517–6524 (2006).
5.
Bernard BA, Bailly C, Lenoir MC, Darmon M, Thierry F, Yaniv M: The human papillomavirus type 18 (HPV18) E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J Virol 63:4317–4324 (1989).
6.
Bertelsen BI, Steine SJ, Sandvei R, Molven A, Laerum OD: Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. Int J Cancer 118:1877–1883 (2006).
7.
Blanton RA, Coltrera MD, Gown AM, Halbert CL, McDougall JK: Expression of the HPV16 E7 gene generates proliferation in stratified squamous cell cultures which is independent of endogenous p53 levels. Cell Growth Differ 3:791–802 (1992).
8.
Boddington MM, Spriggs AI, Wolfendale MR: Cytogenetic abnormalities in carcinoma-in-situ and dysplasias of the uterine cervix. Br Med J 1:154–158 (1965).
9.
Bosch FX, Burchell AN, Schiffman M, Giuliano AR, de Sanjose S, et al: Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine 26:K1–K16 (2008).
10.
Cannizzaro LA, Dürst M, Mendez MJ, Hecht BK, Hecht F: Regional chromosome localization of human papillomavirus integration sites near fragile sites, oncogenes, and cancer chromosome breakpoints. Cancer Genet Cytogenet 33:93–98 (1988).
11.
Cattani P, Hohaus S, Bellacosa A, Genuardi M, Cavallo S, et al: Association between cyclin D1 (CCND1) gene amplification and human papillomavirus infection in human laryngeal squamous cell carcinoma. Clin Cancer Res 4:2585–2589 (1998).
12.
Cheng S, Schmidt-Grimminger DC, Murant T, Broker TR, Chow LT: Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev 9:2335–2349 (1995).
13.
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 161:259–261 (1987).
14.
Cooper K, Herrington CS, Stickland JE, Evans MF, McGee JO: Episomal and integrated human papillomavirus in cervical neoplasia shown by non-isotopic in situ hybridisation. J Clin Pathol 44:990–996 (1991).
15.
Crum CP, Ikenberg H, Richart RM, Gissman L: Human papillomavirus type 16 and early cervical neoplasia. N Engl J Med 310:880–883 (1984).
16.
de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H: Classification of papillomaviruses. Virology 324:17–27 (2004).
17.
DeFilippis RA, Goodwin EC, Wu L, DiMaio D: Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. J Virol 77:1551–1563 (2003).
18.
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 USA 91:4382–4386 (1994).
19.
Deng W, Tsao SW, Kwok YK, Wong E, Huang XR, et al: Transforming growth factor beta1 promotes chromosomal instability in human papillomavirus 16 E6E7-infected cervical epithelial cells. Cancer Res 68:7200–7209 (2008).
20.
Dowhanick JJ, McBride AA, Howley PM: Suppression of cellular proliferation by the papillomavirus E2 protein. J Virol 69:7791–7799 (1995).
21.
Duensing S, Münger K: The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability. Cancer Res 62:7075–7082 (2002).
22.
Duensing S, Lee LY, Duensing A, Basile J, Piboonniyom S, et al: The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle. Proc Natl Acad Sci USA 97:10002–10007 (2000).
23.
Duensing S, Duensing A, Crum CP, Münger K: Human papillomavirus type 16 E7 oncoprotein-induced abnormal centrosome synthesis is an early event in the evolving malignant phenotype. Cancer Res 61:2356–2360 (2001a).
24.
Duensing S, Duensing A, Flores ER, Do A, Lambert PF, Münger K: Centrosome abnormalities and genomic instability by episomal expression of human papillomavirus type 16 in raft cultures of human keratinocytes. J Virol 75:7712–7716 (2001b).
25.
Duensing A, Chin A, Wang L, Kuan SF, Duensing S: Analysis of centrosome overduplication in correlation to cell division errors in high-risk human papillomavirus (HPV)-associated anal neoplasms. Virology 372:157–164 (2008).
26.
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 74:2679–2686 (2000).
27.
Gabet AS, Accardi R, Bellopede A, Popp S, Boukamp P, et al: Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38. FASEB J 22:622–632 (2008).
28.
Gagne SE, Jensen R, Polvi A, Da Costa M, Ginzinger D, et al: High-resolution analysis of genomic alterations and human papillomavirus integration in anal intraepithelial neoplasia. J Acquir Immune Defic Syndr 40:182–189 (2005).
29.
Giampieri S, Storey A: Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18. Br J Cancer 90:2203–2209 (2004).
30.
Giannoudis A, Evans MF, Southern SA, Herrington CS: Basal keratinocyte tetrasomy in low-grade squamous intra-epithelial lesions of the cervix is restricted to high and intermediate risk HPV infection but is not type-specific. Br J Cancer 82:424–428 (2000).
31.
Goodwin EC, DiMaio D: Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci USA 97:12513–12518 (2000).
32.
Halbert CL, Demers GW, Galloway DA: The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells. J Virol 65:473–478 (1991).
33.
Hammes LS, Tekmal RR, Naud P, Edelweiss MI, Kirma N, et al: Macrophages, inflammation and risk of cervical intraepithelial neoplasia (CIN) progression-clinicopathological correlation. Gynecol Oncol 105:157–165 (2007).
34.
Havre PA, Yuan J, Hedrick L, Cho KR, Glazer PM: p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. Cancer Res 55:4420–4424 (1995).
35.
Heilman SA, Nordberg JJ, Liu Y, Sluder G, Chen JJ: Abrogation of the postmitotic checkpoint contributes to polyploidization in human papillomavirus E7-expressing cells. J Virol 83:2756–2764 (2009).
36.
Herbst LH, Lenz J, Van Doorslaer K, Chen Z, Stacy BA, et al: Genomic characterization of two novel reptilian papillomaviruses, Chelonia mydas papillomavirus 1 and Caretta caretta papillomavirus 1. Virology 383:131–135 (2009).
37.
Herdman MT, Pett MR, Roberts I, Alazawi WO, Teschendorff AE, et al: Interferon-beta treatment of cervical keratinocytes naturally infected with human papillomavirus 16 episomes promotes rapid reduction in episome numbers and emergence of latent integrants. Carcinogenesis 27:2341–2353 (2006).
38.
Heselmeyer K, Schröck E, du Manoir S, Blegen H, Shah K, et al: Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. Proc Natl Acad Sci USA 93:479–484 (1996).
39.
Hiraku Y, Tabata T, Ma N, Murata M, Ding X, Kawanishi S: Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection. Cancer Sci 98:964–972 (2007).
40.
Howie HL, Katzenellenbogen RA, Galloway DA: Papillomavirus E6 proteins. Virology 384:324–334 (2009).
41.
Howley PM, Lowy DR: Papillomaviruses, in Knipe DM, Howley PM (eds): Fields Virology, 5th edition (Lippincott Williams & Wilkins, Philadelphia 2007).
42.
Jeon S, Allen-Hoffmann BL, Lambert PF: Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells. J Virol 69:2989–2997 (1995).
43.
Kadaja M, Sumerina A, Verst T, Ojarand M, Ustav E, Ustav M: Genomic instability of the host cell induced by the human papillomavirus replication machinery. EMBO J 26:2180–2191 (2007).
44.
Kadaja M, Isok-Paas H, Laos T, Ustav E, Ustav M: Mechanism of genomic instability in cells infected with the high-risk human papillomaviruses. PLoS Pathog 5:e1000397 (2009).
45.
Kessis TD, Slebos RJ, Nelson WG, Kastan MB, Plunkett BS, et al: Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. Proc Natl Acad Sci USA 90:3988–3992 (1993).
46.
Kessis TD, Connolly DC, Hedrick L, Cho KR: Expression of HPV16 E6 or E7 increases integration of foreign DNA. Oncogene 13:427–431 (1996).
47.
Kobayashi A, Weinberg V, Darragh T, Smith-McCune K: Evolving immunosuppressive microenvironment during human cervical carcinogenesis. Mucosal Immunol 1:412–420 (2008).
48.
Kristiansen E, Jenkins A, Holm R: Coexistence of episomal and integrated HPV16 DNA in squamous cell carcinoma of the cervix. J Clin Pathol 47:253–256 (1994).
49.
Lembo D, Donalisio M, Cornaglia M, Azzimonti B, Demurtas A, Landolfo S: Effect of high-risk human papillomavirus oncoproteins on p53R2 gene expression after DNA damage. Virus Res 122:189–193 (2006).
50.
Lin WM, Michalopulos EA, Dhurander N, Cheng PC, Robinson W, et al: Allelic loss and microsatellite alterations of chromosome 3p14.2 are more frequent in recurrent cervical dysplasias. Clin Cancer Res 6:1410–1414 (2000).
51.
Liu Y, Heilman SA, Illanes D, Sluder G, Chen JJ: p53-independent abrogation of a postmitotic checkpoint contributes to human papillomavirus E6-induced polyploidy. Cancer Res 67:2603–2610 (2007).
52.
Longworth MS, Laimins LA: Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev 68:362–372 (2004).
53.
Männik A, Rünkorg K, Jaanson N, Ustav M, Ustav E: Induction of the bovine papillomavirus origin ‘onion skin’-type DNA replication at high E1 protein concentrations in vivo. J Virol 76:5835–5845 (2002).
54.
Mazibrada J, Rittà M, Mondini M, De Andrea M, Azzimonti B, et al: Interaction between inflammation and angiogenesis during different stages of cervical carcinogenesis. Gynecol Oncol 108:112–120 (2008).
55.
McLaughlin-Drubin ME, Münger K: The human papillomavirus E7 oncoprotein. Virology 384:335–344 (2009).
56.
McMurray HR, Nguyen D, Westbrook TF, McAnce DJ: Biology of human papillomaviruses. Int J Exp Pathol 82:15–33 (2001).
57.
Méhes G, Speich N, Bollmann M, Bollmann R: Chromosomal aberrations accumulate in polyploid cells of high-grade squamous intraepithelial lesions (HSIL). Pathol Oncol Res 10:142–148 (2004).
58.
Moreno-Lopez J, Ahola H, Stenlund A, Osterhaus A, Pettersson U: Genome of an avian papillomavirus. J Virol 51:872–875 (1984).
59.
Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R: The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63:4417–4421 (1989).
60.
Pan H, Griep AE: Temporally distinct patterns of p53-dependent and p53-independent apoptosis during mouse lens development. Genes Dev 9:2157–2169 (1995).
61.
Pett M, Coleman N: Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 212:356–367 (2007).
62.
Pett MR, Alazawi WO, Roberts I, Dowen S, Smith DI, Stanley MA, Coleman N: Acquisition of high-level chromosomal instability is associated with integration of human papillomavirus type 16 in cervical keratinocytes.Cancer Res 64:1359–1368 (2004).
63.
Plug-DeMaggio AW, Sundsvold T, Wurscher MA, Koop JI, Klingelhutz AJ, McDougall JK: Telomere erosion and chromosomal instability in cells expressing the HPV oncogene 16E6. Oncogene 23:3561–3571 (2004).
64.
Rao PH, Arias-Pulido H, Lu XY, Harris CP, Vargas H, et al: Chromosomal amplifications, 3q gain and deletions of 2q33–q37 are the frequent genetic changes in cervical carcinoma. BMC Cancer 4:5 (2004).
65.
Rey O, Lee S, Park NH: Impaired nucleotide excision repair in UV-irradiated human oral keratinocytes immortalized with type 16 human papillomavirus genome. Oncogene 18:6997–7001 (1999).
66.
Romanczuk H, Thierry F, Howley PM: Mutational analysis of cis elements involved in E2 modulation of human papillomavirus type 16 P97 and type 18 P105 promoters. J Virol 64:2849–2859 (1990).
67.
Schlecht NF, Kulaga S, Robitaille J, Ferreira S, Santos M, et al: Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 286:3106–3114 (2001).
68.
Shin KH, Ahn JH, Kang MK, Lim PK, Yip FK, Baluda MA, Park NH: HPV-16 E6 oncoprotein impairs the fidelity of DNA end-joining via p53-dependent and -independent pathways. Int J Oncol 28:209–215 (2006).
69.
Sokolova I, Algeciras-Schimnich A, Song M, Sitailo S, Policht F, et al: Chromosomal biomarkers for detection of human papillomavirus associated genomic instability in epithelial cells of cervical cytology specimens. J Mol Diagn 9:604–611 (2007).
70.
Song S, Gulliver GA, Lambert PF: Human papillomavirus type 16 E6 and E7 oncogenes abrogate radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways. Proc Natl Acad Sci USA 95:2290–2295 (1998).
71.
Southern SA, Evans MF, Herrington CS: Basal cell tetrasomy in low-grade cervical squamous intraepithelial lesions infected with high-risk human papillomaviruses. Cancer Res 57:4210–4213 (1997).
72.
Southern SA, Noya F, Meyers C, Broker TR, Chow LT, Herrington CS: Tetrasomy is induced by human papillomavirus type 18 E7 gene expression in keratinocyte raft cultures. Cancer Res 61:4858–4863 (2001).
73.
Spardy N, Covella K, Cha E, Hoskins EE, Wells SI, Duensing A, Duensing S: Human papillomavirus 16 E7 oncoprotein attenuates DNA damage checkpoint control by increasing the proteolytic turnover of claspin. Cancer Res 69:7022–7029 (2009).
74.
Srivenugopal KS, Ali-Osman F: The DNA repair protein, O(6)-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein. Oncogene 21:5940–5945 (2002).
75.
Stanley MA, Browne HM, Appleby M, Minson AC: Properties of a non-tumorigenic human cervical keratinocyte cell line. Int J Cancer 43:672–676 (1989).
76.
Steenbergen RD, Hermsen MA, Walboomers JM, Joenje H, Arwert F, Meijer CJ, Snijders PJ: Integrated human papillomavirus type 16 and loss of heterozygosity at 11q22 and 18q21 in an oral carcinoma and its derivative cell line. Cancer Res 55:5465–5471 (1995).
77.
Steenbergen RD, Kramer D, Meijer CJ, Walboomers JM, Trott DA, et al: Telomerase suppression by chromosome 6 in a human papillomavirus type 16-immortalized keratinocyte cell line and in a cervical cancer cell line. J Natl Cancer Inst 93:865–872 (2001).
78.
Therrien JP, Drouin R, Baril C, Drobetsky EA: Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair. Proc Natl Acad Sci USA 96:15038–15043 (1999).
79.
Thomas JT, Laimins LA: Human papillomavirus oncoproteins E6 and E7 independently abrogate the mitotic spindle checkpoint. J Virol 72:1131–1137 (1998).
80.
Thorland EC, Myers SL, Gostout BS, Smith DI: Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. Oncogene 22:1225–1237 (2003).
81.
Trottier H, Burchell AN: Epidemiology of mucosal human papillomavirus infection and associated diseases. Public Health Genomics 12:291–307 (2009).
82.
van Duin M, Steenbergen RD, de Wilde J, Helmerhorst TJ, Verheijen RH, et al: Telomerase activity in high-grade cervical lesions is associated with allelic imbalance at 6Q14–22. Int J Cancer 105:577–582 (2003).
83.
Veldman T, Horikawa I, Barrett JC, Schlegel R: Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J Virol 75:4467–4472 (2001).
84.
Wakonig-Vaartaja R, Hughes DT: Chromosomal anomalies in dysplasia, carcinoma-in-situ, and carcinoma of cervix uteri. Lancet 2:756–759 (1965).
85.
Wei L, Gravitt PE, Song H, Maldonado AM, Ozbun MA: Nitric oxide induces early viral transcription coincident with increased DNA damage and mutation rates in human papillomavirus-infected cells. Cancer Res 69:4878–4884 (2009).
86.
Wentzensen N, Vinokurova S, von Knebel Doeberitz M: Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res 64:3878–3884 (2004).
87.
White AE, Livanos EM, Tlsty TD: Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev 8:666–677 (1994).
88.
Wilting SM, Snijders PJ, Meijer GA, Ylstra B, van den Ijssel PR, et al: Increased gene copy numbers at chromosome 20q are frequent in both squamous cell carcinomas and adenocarcinomas of the cervix. J Pathol 209:220–230 (2006).
89.
Wilting SM, Smeets SJ, Snijders PJ, van Wieringen WN, van de Wiel MA, et al: Genomic profiling identifies common HPV-associated chromosomal alterations in squamous cell carcinomas of cervix and head and neck. BMC Med Genomics 2:32 (2009a).
90.
Wilting SM, Steenbergen RD, Tijssen M, van Wieringen WN, Helmerhorst TJ, et al: Chromosomal signatures of a subset of high-grade premalignant cervical lesions closely resemble invasive carcinomas. Cancer Res 69:647–655 (2009b).
91.
Wistuba II, Montellano FD, Milchgrub S, Virmani AK, Behrens C, et al: Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma. Cancer Res 57:3154–3158 (1997).
92.
Zhang A, Wang J, Zheng B, Fang X, Angström T, et al: Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix. Oncogene 23:7441–7447 (2004).
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.