The role of human papillomaviruses in cancer progression

Abstract

The importance of human papillomavirus (HPV) infection and its role in the progress of cancer have been widely evaluated. The understanding of HPV association with certain cancers, such as cervical cancer, is very well established. A big step forward in the prevention of HPV associated cancers with the use of early detection by screening strategies has also been taken. In the last decade, development of HPV vaccination has reduced the number of cases in HPV infections and infection induced cancers. In this report, we review the HPV pathogenesis and highlight the mechanism of HPV involvement in cancer development.

Keywords

Human papillomavirus / cancer / immune response / human papillomavirus vaccine

References

[1] Munoz N,de Sanjosé S,Castellsagué X,Snijders PJ.Epidemiologic classification of human papillomavirus types associated with cervical cancer..N Engl J Med2003;348:518-27

[2] Schiffman M,Buonaguro FM.Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline..Infect Agent Cancer2009;4:8 PMCID:PMC2694995

[3] Hafkamp HC,Speel EJ.Role of human papillomavirus in the development of head and neck squamous cell carcinomas..Acta Otolaryngol2004;124:520-6

[4] Devaraj K,Wu TC.Development of HPV vaccines for HPV-associated head and neck squamous cell carcinoma..Crit Rev Oral Biol Med2003;14:345-62

[5] Bernard HU,Chen Z,zur Hausen H.Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments..Virology2010;401:70-9 PMCID:PMC3400342

[6] Doorbar J.Molecular biology of human papillomavirus infection and cervical cancer..Clin Sci (Lond)2006;110:525-41

[7] Bosch FX,Schiffman M,de Sanjose S,Tortolero-Luna G,Muñoz N.Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia..Vaccine2008;26 Suppl 10:K1-16

[8] Ekström J,Svenback D,Dillner J.High throughput sequencing reveals diversity of Human Papillomaviruses in cutaneous lesions..Int J Cancer2011;129:2643-50

[9] de Villiers EM,Broker TR,zur Hausen H.Classification of papillomaviruses..Virology2004;324:17-27

[10] Doorbar J,Banks L,Stoler M,Stanley MA.The biology and life-cycle of human papillomaviruses..Vaccine2012;30 Suppl 5:F55-70

[11] zur Hausen H.Human papillomaviruses in the pathogenesis of anogenital cancer..Virology1991;184:9-13

[12] Biedermann K,Trattner M,Doppelmayr H,Staudach A,Hauser-Kronberger C.Comparison of real-time PCR signal-amplified in situ hybridization and conventional PCR for detection and quantification of human papillomavirus in archival cervical cancer tissue..J Clin Microbiol2004;42:3758-65 PMCID:PMC497646

[13] Middleton K,Southern S,Sotlar K,El-Sherif A,Seth R,Jenkins D,Coleman N.Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers..J Virol2003;77:10186-201 PMCID:PMC228472

[14] Cogliano V,Straif K,Secretan B,WHO International Agency for Research on Cancer..Carcinogenicity of human papillomaviruses..Lancet Oncol2005;6:204

[15] Nindl I,Stockfleth E.Human papillomaviruses and non-melanoma skin cancer: basic virology and clinical manifestations..Dis Markers2007;23:247-59 PMCID:PMC3851066

[16] Gottschling M,Köhler A,Stockfleth E.Cutaneotropic human beta-/gamma-papillomaviruses are rarely shared between family members..J Invest Dermatol2009;129:2427-34

[17] Bottalico D,Dunne A,McKinney S,Schlecht NF,Herrero R,Burk RD.The oral cavity contains abundant known and novel human papillomaviruses from the Betapapillomavirus and Gammapapillomavirus genera..J Infect Dis2011;204:787-92 PMCID:PMC3156102

[18] Chow KY1,Ben Khalifa Y,Teissier S,Galzi JL,Thierry F.A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome..Cell Host Microbe2010;8:523-33

[19] Lazarczyk M,Pons C,Favre M.The EVER proteins as a natural barrier against papillomaviruses: a new insight into the pathogenesis of human papillomavirus infections..Microbiol Mol Biol Rev2009;73:348-70 PMCID:PMC2698414

[20] Gulino AV.WHIM syndrome: a genetic disorder of leukocyte trafficking..Curr Opin Allergy Clin Immunol2003;3:443-50

[21] Ortak T,Alagoz MS,Sensoz O.Epidermodysplasia verruciformis: an unusual presentation..Dermatol Surg2006;32:302-6

[22] Woodman CB,Young LS.The natural history of cervical HPV infection: unresolved issues..Nat Rev Cancer2007;7:11-22

[23] Howard JD.Biology of human papillomavirus-related oropharyngeal cancer..Semin Radiat Oncol2012;22:187-93 PMCID:PMC3715056

[24] Beutner KR.Human papillomaviruses and human disease..Am J Med1997;5:9-15

[25] Kjaer SK,van den Brule AJ,Paull G,Schiller JT,Sherman ME,Meijer CL.High-risk human papillomavirus is sexually transmitted: evidence from a follow-up study of virgins starting sexual activity (intercourse)..Cancer Epidemiol Biomarkers Prev2001;10:101-6

[26] Castellsagué X,Daniel RW,Mu-oz N.Prevalence of penile human papillomavirus DNA in husbands of women with and without cervical neoplasia: a study in Spain and Colombia..J Infect Dis1997;176:353-61

[27] Bosch FX,Mu-oz N,Ghaffari AM,Gili M,Viladiu P,Vergara A,Guerrero E.Male sexual behavior and human papillomavirus DNA: key risk factors for cervical cancer in Spain..J Natl Cancer Inst1996;88:1060-7

[28] Cason J.Perinatal acquisition of cervical cancer-associated papillomaviruses..Br J Obstet Gynaecol1996;103:853-8

[29] Favre M,De Jesus N,Orth G.A possible vertical transmission of human papillomavirus genotypes associated with epidermodysplasia verruciformis..J Invest Dermatol1998;111:333-6

[30] Bosch FX,Castellsagué X.The epidemiology of human papillomavirus infection and its association with cervical cancer..Int J Gynecol Obstet2006;94:S8-21

[31] Stern PL.From HPV infection to oncogenesis: a brief review of the complex immunobiological events..Curr Cancer Ther Rev2010;110-6

[32] van der Burg SH.Melief, Therapeutic vaccination against human papilloma virus induced malignancies..Curr Opin Immunol2011;23:252-7

[33] Hanahan D.Hallmarks of cancer: the next generation..Cell2011;144:646-74

[34] Laffort C,Favre M,Radford-Weiss I,Fraitag S,Cavazzana-Calvo M,de Villartay JP,Orth G,Bodemer C.Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency..Lancet2004;363:2051-4

[35] Gewirtzman A,Tyring S.Epidermodysplasia verruciformis and human papilloma virus..Curr Opin Infect Dis2008;21:141-6

[36] Dubina M.Viral-associated nonmelanoma skin cancers: a review..Am J Dermatopathol2009;31:561-73

[37] Weissenborn S,Waterboer T,Bavinck JN,Harwood CA,Feltkamp MC,Naldi L,Tessari G,Wieland U.Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients..Med Microbiol Immunol2012;201:117-25

[38] Kanodia S,Kast WM.Mechanisms used by human papillomaviruses to escape the host immune response..Curr Cancer Drug Targets2007;7:79-89

[39] O'Brien PM.Evasion of host immunity direct by papillomavirus-encoded proteins..Virus Res2002;88:103-17

[40] de Sanjose S,Alemany L,Klaustermeier JE,Tous S,Bravo LE,Vallejos CS,Lima MA,Clavero O,Llombart-Bosch A,Tatti SA,Iljazovic E,Prado R,Grce M,Jain A,Lombardi LE,Menéndez C,Velasco J,Chichareon SC,Lerma E,Sasagawa T,Hammouda D,Pelayo A,Oliva E,Al-Jassar WF,Wright TC,Llave CL,Agorastos T,Clavel C,Andújar M,Sánchez GI,Bornstein J,Bosch FX.Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study..Lancet Oncol2010;11:1048-56

[41] Ryser MD,Durrett R.HPV Clearance and the Neglected Role of Stochasticity..PLoS Comput Biol2015;11:e1004113

[42] Stern PL,Hampson IN,Fiander A,Kitchener HC.Therapy of human papillomavirus-related disease..Vaccine2012;30 Suppl 5:F71-82

[43] Future II Study Group..Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions..N Engl J Med2007;356:1915-27

[44] Garland SM,Wheeler CM,Harper DM,Tang GW,Steben M,Taddeo FJ,Esser MT,Nelson M,Sattler C,Koutsky LA.Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases..N Engl J Med2007;356:1928-43

[45] Choi YH,Gay N.Potential overestimation of HPV vaccine impact due to unmasking of non-vaccine types: quantification using a multi-type mathematical model..Vaccine2012;30:3383-8

[46] Wheeler CM,Sigurdsson K,Hernandez-Avila M,Brown DR,Tay EH,Ault KA,Leodolter S,Tang GW,Paavonen J,Bosch FX,Joura EA,Majewski S,Myers ER,Taddeo FJ,Tadesse A,Lupinacci LC,James M,Hesley TM.The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years..J Infect Dis2009;199:936-44

[47] Aggarwal P.Cervical cancer: Can it be prevented?.World J Clin Oncol2014;5:775-80

[48] Schiller JT,Garland SM.A review of clinical trials of human papillomavirus prophylactic vaccines..Vaccine2012;30 Suppl 5:F123-38

[49] Donovan B,Guy R,Regan DG,Wand H.Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data..Lancet Infect Dis2011;11:39-44

[50] Future II Study Group..Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions..N Engl J Med2007;356:1915-27

[51] Kjær SK,Munk C.Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence..J Natl Cancer Inst2010;102:1478-88 PMCID:PMC2950170

[52] Forman D,Lacey CJ,Lortet-Tieulent J,Vignat J,Bray F,Franceschi S.Global burden of human papillomavirus and related diseases..Vaccine2012;30 Suppl 5:F12-23

[53] de Sanjosé S. Human Papillomavirus and cancer. Epidemiology and prevention. 4th monograph of the Spanish Society of Epidemiology. Barcelona, Spain: Spanish Society of Epidemiology; 2006. pp. 143–7.

[54] zur Hausen H.Papillomaviruses in the causation of human cancers - a brief historical account..Virology2009;384:260-5

[55] Walboomers JM,Manos MM,Kummer JA,Snijders PJ,Meijer CJ.Human papillomavirus is a necessary cause of invasive cervical cancer worldwide..J Pathol1999;189:12-9

[56] Abramowitz L,Jaroud F,Siproudhis L,Aynaud O,Soubeyrand B,Riethmuller D,Pretet JL.Human papillomavirus genotype distribution in anal cancer in France: the EDiTH V study..Int J Cancer2011;129:433-9

[57] De Vuyst H,Nascimento MC,Franceschi S.Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis..Int J Cancer2009;124:1626-36

[58] Miralles-Guri C,Cubilla AL,Bosch FX.Human papillomavirus prevalence and type distribution in penile carcinoma..J Clin Pathol2009;62:870-8

[59] St Guily JL,Prétet JL,Beby-Defaux A,Agius G,Okaïs C,Soubeyrand B,Riethmuller D,Denis F.Human papillomavirus genotype distribution in oropharynx and oral cavity cancer in France--The EDiTH VI study..J Clin Virol2011;51:100-4

[60] Grayson W,Taylor LF,Tiltman AJ.Detection of human papillomavirus in large cell neuroendocrine carcinoma of the uterine cervix: a study of 12 cases..J Clin Pathol2002;55:108-14 PMCID:PMC1769596

[61] Gravitt PE,Brinton LA,Kornegay JR,Greene SM,McGowan L,Schwartz PE,Hildesheim A.Evaluation of self-collected cervicovaginal cell samples for human papillomavirus testing by polymerase chain reaction..Cancer Epidemiol Biomarkers Prev2001;10:95-100

[62] Bouvard V,Grosse Y,El Ghissassi F,Guha N.Carcinogenicity of malaria and of some polyomaviruses..Lancet Oncol2012;13:339-40

[63] Egawa K.Do human papillomaviruses target epidermal stem cells?.Dermatology2003;207:251-4

[64] Schmitt A,Zeltner R,Barrandon Y,Iftner T.The primary target cells of the high-risk cottontail rabbit papillomavirus colocalize with hair follicle stem cells..J Virol1996;70:1912-22

[65] Kim K.E1 protein of bovine papillomavirus 1 is not required for the maintenance of viral plasmid DNA replication..Virology2002;293:10-4

[66] Angeletti PC,Fernandes FJ.Stable replication of papillomavirus genomes in Saccharomyces cerevisiae..J Virol2002;76:3350-8 PMCID:PMC136042

[67] McBride AA.Replication and partitioning of papillomavirus genomes..Adv Virus Res2008;72:155-205

[68] Blakaj DM,Chen Z,Fiser A,Brenowitz M.Evolutionary and biophysical relationships among the papillomavirus E2 proteins..Front Biosci (Landmark Ed)2009;14:900-17 PMCID:PMC3705561

[69] Chung CH.Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications..Clin Cancer Res2009;15:6758-62

[70] Valencia C,Oktaba K,Gariglio P.Human papillomavirus E6/E7 oncogenes promote mouse ear regeneration by increasing the rate of wound re-epithelization and epidermal growth..J Invest Dermatol2008;128:2894-903

[71] Klingelhutz AJ.Cellular transformation by human papillomaviruses: lessons learned by comparing high- and low-risk viruses..Virology2012;424:77-98 PMCID:PMC3703738

[72] von Knebel Doeberitz M.New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections..Eur J Cancer2002;38:2229-42

[73] Moody CA.Human papillomavirus oncoproteins: pathways to transformation..Nat Rev Cancer2010;10:550-60

[74] Agger K,Rudkjaer L,Andersen G,Helin K.The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence..Genes Dev2009;23:1171-6 PMCID:PMC2685535

[75] Barradas M,Acosta JC,Banito A,Maertens G,Zhou MM,Peters G.Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS..Genes Dev2009;23:1177-82 PMCID:PMC2685533

[76] Gonzalez SL,He X,Münger K.Degradation of the retinoblastoma tumor suppressor by the human papillomavirus type 16 E7 oncoprotein is important for functional inactivation and is separable from proteasomal degradation of E7..J Virol2001;75:7583-91 PMCID:PMC114993

[77] Duensing S.Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins..Int J Cancer2004;109:157-62

[78] Lowy DR.Reducing HPV-associated cancer globally..Cancer Prev Res (Phila)2012;5:18-23 PMCID:PMC3285475

[79] Wikström A,Syrjänen S.Penile intraepithelial neoplasia: histopathological evaluation, HPV typing, clinical presentation and treatment..J Eur Acad Dermatol Venereol2012;26:325-30

[80] Silva RJ,Andreoli MA.Persistence and clearance of HPV from the penis of men infected and non-infected with HIV..J Med Virol2011;83:127-31

[81] Szentirmay Z,Tamás L,Kurcsics J,Tóth E.Human papillomavirus in head and neck cancer: molecular biology and clinicopathological correlations..Cancer Metastasis Rev2005;24:19-34

[82] Syrjänen K,Lamberg M,Nuutinen J.Morphological and immunohistochemical evidence suggesting human papillomavirus (HPV) involvement in oral squamous cell carcinogenesis..Int J Oral Surg1983;12:418-24

[83] Harper DM.Primary strategies for HPV infection and cervical cancer prevention..Clin Obstet Gynecol2014;57:256-78

[84] Bosch FX,Forman D,Gillison ML,Stern PL,Arbyn M,Cuzick J,Schiller JT,Fisher WA,Denny LA,Steben M,Schiffman M,Sankaranarayanan R,Kim JJ,Alemany L,Diaz M.Comprehensive control of human papillomavirus infections and related diseases..Vaccine2013;31 Suppl 8:I1-31

[85] Bosch FX,Mu-oz N,Shah KV.The causal relation between human papillomavirus and cervical cancer..J Clin Pathol2002;55:244-65 PMCID:PMC1769629

[86] Schiffman M.Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia.J Natl Cancer Inst Monogr2003;14-9

[87] Wen LM,Simpson JM.Risk factors for the acquisition of genital warts: are condoms protective?.Sex Transm Infect1999;75:312-6

[88] Münger K.Human papillomavirus immortalization and transformation functions..Virus Res2002;89:213-28

[89] Klaes R,Ridder R,Duerst M,Lotz B,von Knebel Doeberitz M.Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes..Cancer Res1999;59:6132-6

[90] Li K,Fang Y,Gong M,Liu J,Ai J.Correlation between physical status of human papilloma virus and cervical carcinogenesis..J Huazhong Univ Sci Technol Med Sci2012;32:97-102

[91] Baseman JG.The epidemiology of human papillomavirus infections..J Clin Virol2005;32 Suppl 1:S16-24

[92] Melsheimer P,Wentzensen N,von Knebel Doeberitz M.DNA aneuploidy and integration of human papillomavirus type 16 e6/e7 oncogenes in intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix uteri..Clin Cancer Res2004;10:3059-63

[93] Häfner N,Gajda M,Kirchmayr R,Dürst M.Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts..Oncogene2008;27:1610-7

[94] Paavonen J,Bosch FX,Salmerón J,Chow SN,Kitchener HC,de Carvalho NS,Harper DM,Jaisamrarn U,Dionne M,Spiessens B,Struyf F,Lehtinen MO.Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial..Lancet2007;369:301-14

[95] Paavonen J,Salmerón J,Chow SN,Kitchener H,Teixeira JC,Hedrick J,Limson G,Szarewski A,Aoki FY,Poppe WA,Jenkins D,Zahaf T,Struyf F,Dubin G.Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women..Lancet2009;374:301-14

[96] Szarewski A,Skinner SR,Paavonen J,Salmeron J,Apter D,Castellsagué X,Hedrick J,Limson G,Romanowski B,Schwarz TF,Harper DM,Zahaf T,Struyf F,Dubin G.Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18..Int J Cancer2012;131:106-16

[97] Quint W,Molijn A,van de Sandt M,Mols J,Hardt K,Colau B.One virus one lesion - Individual components of CIN lesions contain a specific HPV type..J Pathol2012;227:449-65

[98] Gariglio P,Cortés E.The role of retinoid deficiency and estrogens as cofactors in cervical cancer..Arch Med Res2009;40:449-65

[99] Ding DC,Lai HC,Hsieh CY.Methylation of the long control region of HPV16 is related to the severity of cervical neoplasia..Eur J Obstet Gynecol Reprod Biol2009;147:215-29

[100] van de Nieuwenhof HP,van der Avoort IA,Casparie M,van Kempen LC.Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age..Eur J Cancer2009;45:851-6

[101] Wright TCJr,Dunton CJ,Wilkinson EJ,2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference..2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests..Am J Obstet Gynecol2007;197:346-55

[102] Ambrosio MR,Rocca BJ.Vulvar cancer and HPV infection: analysis of 22 cases..Pathologica2008;100:405-7

[103] Gormley RH.Human papillomavirus-related genital disease in the immunocompromised host: Part I..J Am Acad Dermatol2012;66:867.e1-14; quiz 881-2

[104] Bosch FX,Forman D,Gillison ML,Stern PL,Arbyn M,Cuzick J,Schiller JT,Fisher WA,Denny LA,Steben M,Schiffman M,Sankaranarayanan R,Kim JJ,Alemany L,Diaz M,authors of ICO Monograph Comprehensive Control of HPV Infections and Related Diseases Vaccine Volume 30, Supplement 5, 2012..Comprehensive control of human papillomavirus infections and related diseases..Vaccine2013;31 Suppl 7:H1-31

[105] Antonsson A,Chen AC,McMillan NA,Law M.High prevalence of human papillomaviruses in fresh frozen breast cancer samples..J Med Virol2011;83:2157-63

[106] Khan NA,Koriyama C,Umekita Y,Higashi M,Yoshinaka H,Natsugoe S,Eizuru Y.Human papillomavirus detected in female breast carcinomas in Japan..Br J Cancer2008;99:408-14 PMCID:PMC2527789

[107] Kroupis C,Vourlidis N,Lianidou ES.Presence of high-risk human papillomavirus sequences in breast cancer tissues and association with histopathological characteristics..Clin Biochem2006;39:727-31

[108] Lawson JS,Whitaker NJ.Viruses and human breast cancer..Future Microbiol2006;1:33-51

[109] Frega A,Bononi M,Ciardi A,Assorgi C,Moscarini M,French D.Evaluation of E6 and E7 mRNA expression in HPV DNA positive breast cancer..Eur J Gynaecol Oncol2012;33:164-7

[110] Jemal A,Center MM,Ward E.Global cancer statistics..CA Cancer J Clin2011;61:69-90

[111] Chaturvedi AK,Pfeiffer RM,Xiao W,Jiang B,Sibug-Saber M,Liu L,Wentzensen N,Altekruse S,Rosenberg PS.Human papillomavirus and rising oropharyngeal cancer incidence in the United States..J Clin Oncol2011;29:4294-301 PMCID:PMC3221528

[112] Arbyn M,Saraiya M,Palefsky J,Gillison M,Ronco G,Brotherton J,Denny L,Abramowitz L,Tommasino M.EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease..Int J Cancer2012;131:1969-82 PMCID:PMC3429628

[113] Leemans CR,Brakenhoff RH.The molecular biology of head and neck cancer..Nat Rev Cancer2010;11:9-22

[114] Psychogios G,Agaimy A,Koch M,Tomppert A.Epidemiology and survival of HPV-related tonsillar carcinoma..Cancer Med2014;3:652-9 PMCID:PMC4101756

[115] van Seters M,ten Kate FJ,Ewing PC,Kagie MJ,Aaronson NK,Heijmans-Antonissen C,Burger MP.Treatment of vulvar intraepithelial neoplasia with topical imiquimod..N Engl J Med2008;358:1465-73

[116] Fakhry C,Li S,Ridge JA,Forastiere A.Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial..J Natl Cancer Inst2008;100:261-9

[117] Schache AG,Risk JM,Jones TM,Woolgar JA,Triantafyllou A,Sloan P,Sisson D.Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity, and prognostic discrimination..Clin Cancer Res2011;17:6262-71 PMCID:PMC3188400

[118] Brown LM,Devesa SS.Oropharyngeal cancer incidence trends: diminishing racial disparities..Cancer Causes Control2011;22:753-63

[119] Morshed K.Association between human papillomavirus infection and laryngeal squamous cell carcinoma..J Med Virol2010;82:1017-23

[120] Rodrigo JP,Fresno MF,García-Velasco F,Heideman DA.Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas in northern Spain..Cancer Epidemiol2015;39:37-41

[121] Hernandez BY,Lynch CF,Unger ER,Thompson T,Altekruse SF,Saraiya M.Human papillomavirus prevalence in invasive laryngeal cancer in the United States..PLoS One2014;9:e115931

[122] Syrjänen S,von Bültzingslöwen I,Arduino P,Challacombe S,Flaitz C,Maeda H,Jontell M.Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review..Oral Dis2011;17 Suppl 1:58-72

[123] Nielsen H,Vedtofte P,Reibel J.Human papillomavirus in oral premalignant lesions..Eur J Cancer B Oral Oncol1996;32B:264-70

[124] Szarka K,Fehér E,Kis A,Boda R,Gergely L.Progressive increase of human papillomavirus carriage rates in potentially malignant and malignant oral disorders with increasing malignant potential..Oral Microbiol Immunol2009;24:314-8

[125] Welters MJ,Piersma SJ,Löwik MJ,Drijfhout JW,Wafelman AR,Fleuren GJ,Melief CJ.Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine..Clin Cancer Res2008;14:178-87

[126] Tseng CW,Alvarez RD,Huh WK,Chuang CM,Tsai YC,Monie A.Pretreatment with cisplatin enhances E7-specific CD8+ T-Cell-mediated antitumor immunity induced by DNA vaccination..Clin Cancer Res2008;14:3185-92 PMCID:PMC3066100

[127] Tseng CW,Zeng Q,Alvarez RD,Hoory T,Hung CF.Low-dose radiation enhances therapeutic HPV DNA vaccination in tumor-bearing hosts..Cancer Immunol Immunother2009;58:737-48 PMCID:PMC2647576

[128] Haas AR,Vachani A,Silverberg M,Albelda SM.Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine..Clin Cancer Res2006;12:214-22

[129] Chaturvedi AK,Anderson WF.Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States..J Clin Oncol2008;26:612-9

[130] Hammarstedt L,Dahlstrand H,Dahlgren LO,Creson N,Ye W,Munck-Wikland E.Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer..Int J Cancer2006;119:2620-3

[131] Marur S,Westra WH.HPV-associated head and neck cancer: a virus-related cancer epidemic..Lancet Oncol2010;11:781-9

[132] Krüger M,Walter C,Günther C,Weise K,Ziebart T.The prevalence of human papilloma virus (HPV) infections in oral squamous cell carcinomas: a retrospective analysis of 88 patients and literature overview..J Craniomaxillofac Surg2014;42:1506-14

[133] Ruzevick J,Westra WH.Metastatic squamous cell carcinoma to the brain: an unrecognized pattern of distant spread in patients with HPV-related head and neck cancer..J Neurooncol2013;112:449-54 PMCID:PMC3630253

[134] Wood ME,Mullineaux LG.The inherited nature of lung cancer: a pilot study..Lung Cancer2000;30:135-44

[135] Matakidou A,Houlston RS.TP53 polymorphisms and lung cancer risk: a systematic review and meta-analysis..Mutagenesis2003;18:377-85

[136] Syrjänen K. Papillomavirus infections and cancer Papillomaviruses and Human Disease, ed. K Syrjänen, L Gissmann, LG Koss. 1987, Heidelberg: Springer-Verlag.

[137] Syrjänen KJ.Epithelial lesions suggestive of a condylomatous origin found closely associated with invasive bronchial squamous cell carcinomas..Respiration1980;40:150-60

[138] Trillo A.Solitary condylomatous papillomas of the bronchus..Arch Pathol Lab Med1988;112:731-3

[139] Stremlau A,Ikenberg H,Bannasch P.Human papillomavirus type 16 related DNA in an anaplastic carcinoma of the lung..Cancer1985;55:1737-40

[140] Byrne JC,Fraser RS.Human papillomavirus-11 DNA in a patient with chronic laryngotracheobronchial papillomatosis and metastatic squamous-cell carcinoma of the lung..N Engl J Med1987;317:873-8

[141] Syrjanen KJ.HPV infections and lung cancer..J Clin Pathol2002;55:885-91 PMCID:PMC1769837

[142] Gorgoulis VG,Kotsinas A,Rassidakis AN,Barbatis C,Kittas C.Human papillomavirus (HPV) is possibly involved in laryngeal but not in lung carcinogenesis..Human Pathol1999;30:274-83

[143] Rezazadeh A,Ghim SJ,Kloecker G.The role of human papilloma virus in lung cancer: a review of the evidence..Am J Med Sci2009;338:64-7

[144] Storey R,Kwon A,Ghim SJ.Detection of Immunoglobulin G against E7 of Human Papillomavirus in Non-Small-Cell Lung Cancer..J Oncol2013;2013:240164 PMCID:PMC3603668

[145] Isa SI,Yamamoto S,Omachi N,Okishio K,Ito N,Matsumura A,Kawaguchi T.Molecular analysis of human papillomavirus in never-smokers with non-small cell lung cancer..Oncol Lett2015;9:927-9 PMCID:PMC4301494

[146] Ragin C,Kim S,Flores-Obando R,Koriyama C,Koshiol J,Carpagnano GE,Dosaka-Akita H,Goto A,Gorgoulis V,van Boerdonk RA,Iwakawa R,Kinoshita I,Landi MT,Wang JL,Khuri FR,Owonikoko TK,Sarchianaki E,Tsao MS,Hee SW,Zaravinos A.HPV-associated lung cancers: an international pooled analysis..Carcinogenesis2014;35:1267-75 PMCID:PMC4043241

[147] Zhai K,Shi HZ.HPV and lung cancer risk: a meta-analysis..J Clin Virol2015;63C:84-90

[148] Hsueh PR.Human papillomavirus, genital warts, and vaccines..J Microbiol Immunol Infect2009;42:101-6

[149] Derkay CS.Task force on recurrent respiratory papillomas. A preliminary report..Arch Otolaryngol Head Neck Surg1995;121:1386-91

[150] Omland T,Akre H,Jebsen P,Nymoen DA,Dillner J.Recurrent respiratory papillomatosis: HPV genotypes and risk of high-grade laryngeal neoplasia..PLoS One2014;9:e99114

[151] Major T,Sziklai I,Czeglédy J.The characteristics of human papillomavirus DNA in head and neck cancers and papillomas..J Clin Pathol2005;58:51-5 PMCID:PMC1770542

[152] Bharti AH,Marfatia YS.An update on oral human papillomavirus infection..Indian J Sex Transm Dis2013;34:77-82 PMCID:PMC3841675

[153] Gallagher TQ.Pharmacotherapy of recurrent respiratory papillomatosis: an expert opinion..Expert Opin Pharmacother2009;10:645-55

[154] Kitamura T,Ueki T,Aso Y.Presence of human papillomavirus type 16 genome in bladder carcinoma in situ of a patient with mild immunodeficiency..Cancer Res1988;48:7207-11

[155] Gutiérrez J,de Dios Luna J,Sorlózano A.Meta-analysis of studies analyzing the relationship between bladder cancer and infection by human papillomavirus..J Urol2006;176:2474-81

[156] Griffiths TR.Human papillomavirus and urological tumours: II. Role in bladder, prostate, renal and testicular cancer..BJU Int2000;85:211-7

[157] Youshya S,Breuer J,Sheaf MT,Baithun S.Does human papillomavirus play a role in the development of bladder transitional cell carcinoma? A comparison of PCR and immunohistochemical analysis..J Clin Pathol2005;58:207-10 PMCID:PMC1770580

[158] Lopez-Beltran A,Vicioso L,Carrasco JC.Human papillomavirus DNA as a factor determining the survival of bladder cancer patients..Br J Cancer1996;73:124-7 PMCID:PMC2074275

[159] Sano T,Fukuda T.Unsuccessful effort to detect human papillomavirus DNA in urinary bladder cancers by the polymerase chain reaction and in situ hybridization..Pathol Int1995;45:506-12

[160] Li N,Zhang Y,Zheng T.Human papillomavirus infection and bladder cancer risk: a meta-analysis..J Infect Dis2011;204:217-23 PMCID:PMC3114469

[161] Jimenez-Pacheco A,Arrabal-Polo MA.Meta-analysis of studies analyzing the role of human papillomavirus in the development of bladder carcinoma..Korean J Urol2012;53:240-7 PMCID:PMC3332134

[162] Tenti P,Romagnoli S,Giunta P,Stella G.p53 overexpression and human papillomavirus infection in transitional cell carcinoma of the urinary bladder: correlation with histological parameters..J Pathol1996;178:65-70

[163] Shigehara K,Kawaguchi S,Shimamura M,Konaka H,Koh E.Etiologic role of human papillomavirus infection in bladder carcinoma..Cancer2011;117:2067-76

[164] Moonen PM,Kiemeney LA,Melchers WJ.Human papilloma virus DNA and p53 mutation analysis on bladder washes in relation to clinical outcome of bladder cancer..Eur Urol2007;52:464-8

[165] Kamel D,Pöllänen R,Lehto VP.Human papillomavirus DNA and abnormal p53 expression in carcinoma of the urinary bladder..APMIS1995;103:331-8

[166] Steinestel J,Müller J,Skowronek P,Kraft K,Schrader AJ.Overexpression of p16(INK4a) in urothelial carcinoma in situ is a marker for MAPK-mediated epithelial-mesenchymal transition but is not related to human papillomavirus infection..PLoS One2013;8:e65189

[167] Kim SH,Chung J,Lee KH.Detection of human papillomavirus infection and p16 immunohistochemistry expression in bladder cancer with squamous differentiation..PLoS One2014;9:e93525

[168] Shigehara K,Doorbar J,Kobori Y,Shimamura M,Miyagi T,Kadono Y,Mizokami A,Namiki M.Etiological role of human papillomavirus infection for inverted papilloma of the bladder..J Med Virol2011;83:277-85

[169] Shaker OG,Wishahi MM.Is there a correlation between HPV and urinary bladder carcinoma?.Biomed Pharmacother2013;67:183-91

[170] Alexander RE,Lopez-Beltran A,MacLennan GT,Idrees MT,Cheng L.Human papillomavirus is not an etiologic agent of urothelial inverted papillomas..Am J Surg Pathol2013;37:1223-8

[171] Alexander RE,Lopez-Beltran A,MacLennan GT,Idrees MT,Cheng L.The expression patterns of p53 and p16 and an analysis of a possible role of HPV in primary adenocarcinoma of the urinary bladder..PLoS One2014;9:e95724

[172] Badawi H,Ismail A,Moubarak M,Saber M.Role of human papillomavirus types 16, 18, and 52 in recurrent cystitis and urinary bladder cancer among Egyptian patients..Medscape J Med2008;10:232

[173] Nakashima K,Kawaguchi S,Kobori Y,Ishii Y,Sasagawa T,Mizokami A.Prevalence of human papillomavirus infection in the oropharynx and urine among sexually active men: a comparative study of infection by papillomavirus and other organisms, including Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma spp., and Ureaplasma spp..BMC Infect Dis2014;14:43 PMCID:PMC3907364

[174] Barghi MR,Borghei M,Amani D.Association between the evidence of human papilloma virus infection in bladder transitional cell carcinoma in men and cervical dysplasia in their spouses..Arch Iran Med2012;15:572-4

[175] Berrada N,Ameur A,El-Mzibri M,Benbacer L,Qmichou Z,Attaleb M.Human papillomavirus detection in Moroccan patients with bladder cancer..J Infect Dev Ctries2013;7:586-92

[176] Castellsagué X,Mu-oz N,Shah KV,Eluf-Neto J,Chichareon S,Herrero R,Franceschi S.Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners..N Engl J Med2002;346:1105-12

[177] Bezerra SM,Ball MW,Munari E,Sharma R,Burnett AL.Human papillomavirus infection and immunohistochemical p16 expression as predictors of outcome in penile squamous cell carcinomas..Hum Pathol2015;46:532-40

[178] Lohneis P,Kaufmann AM,Schewe C,Anagnostopoulos I.Human papilloma virus status of penile squamous cell carcinoma is associated with differences in tumour-infiltrating T lymphocytes..Virchows Arch2015;466:323-31

[179] Rubin MA,Zhou M,Cubilla AL,Pirog EC.Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis..Am J Pathol2001;159:1211-8

[180] Giuliano AR,Flores R,Abrahamsen M,Markowitz LE,Harris RB.The optimal anatomic sites for sampling heterosexual men for human papillomavirus (HPV) detection: the HPV detection in men study..J Infect Dis2007;196:1146-52 PMCID:PMC3904649

[181] Schwartz RA.Bowenoid papulosis..J Am Acad Dermatol1991;24:261-4

[182] Chao MW.Squamous cell carcinoma arising in a giant condyloma acuminatum (Buschke-Lowenstein tumour)..Asian J Surg2005;28:238-40

[183] Handisurya A,Bago-Horvath Z,Bankier A,Stingl G.Rapid progression of an anal Buschke-Lowenstein tumour into a metastasising squamous cell carcinoma in an HIV-infected patient..Sex Transm Infect2009;85:261-3 PMCID:PMC3935459

[184] Daling JR.Relationship between human papillomavirus infection and tumours of anogenital sites other than the cervix..IARC Sci Publ1992;(119):223-41

[185] Forslund O,Andersson K,Hradil E,Stenquist B,Dillner J.Cutaneous human papillomaviruses found in sun-exposed skin: Beta-papillomavirus species 2 predominates in squamous cell carcinoma..J Infect Dis2007;196:876-83 PMCID:PMC3795387

[186] Tschandl P,Kittler H.Cutaneous human papillomavirus infection: manifestations and diagnosis..Curr Probl Dermatol2014;45:92-7

[187] Cobb MW.Human papillomavirus infection..J Am Acad Dermatol1990;22:547-66

[188] Wallace NA,Howie HL.HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage..PLoS Pathog2012;8:e1002807

[189] Iftner T,Schopp B,Loizou JI,Stubenrauch F.Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1..EMBO J2002;21:4741-8 PMCID:PMC126183

[190] Iftner A,Garbe C,Stancu A,Iftner T.The prevalence of human papillomavirus genotypes in nonmelanoma skin cancers of nonimmunosuppressed individuals identifies high-risk genital types as possible risk factors..Cancer Res2003;63:7515-9

[191] Andersson K,Kirnbauer R,Iftner T,Forslund O,Dillner J.Seroreactivity to cutaneous human papillomaviruses among patients with nonmelanoma skin cancer or benign skin lesions..Cancer Epidemiol Biomarkers Prev2008;17:189-95

[192] Scarbrough Lefebvre CD,Gonçalves MA.Appraisal of the burden of genital warts from a healthcare and individual patient perspective..Public Health2011;125:464-75

[193] Grce M,Skerlev M,Pavelić K.Detection and typing of human papillomaviruses by means of polymerase chain reaction and fragment length polymorphism in male genital lesions..Anticancer Res2000;20:2097-102

[194] Bhatia N,Vender R.Understanding genital warts: epidemiology, pathogenesis, and burden of disease of human papillomavirus..J Cutan Med Surg2013;17 Suppl 2:S47-54

[195] Ling MR.Therapy of genital human papillomavirus infections. Part I: Indications for and justification of therapy..Int J Dermatol1992;31:682-6

[196] Lacey CJ,Shah KV.Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease.Vaccine2006;24 Suppl 3:S3/35-41

[197] Ljubojevic S.HPV-associated diseases..Clin Dermatol2014;32:227-34

[198] Fathi R.Genital warts and other HPV infections: established and novel therapies..Clin Dermatol2014;32:299-306

[199] Gnanamony M,Abraham P.An overview of human papillomaviruses and current vaccine strategies..Indian J Med Microbiol2007;25:10-7

[200] Remy-Ziller C,Spindler A,Silvestre N,Bonnefoy JY.Immunological characterization of a modified vaccinia virus Ankara vector expressing the human papillomavirus 16 E1 protein..Clin Vaccine Immunol2014;21:147-55 PMCID:PMC3910931