Case–Control Study of Human Papillomavirus and Oropharyngeal Cancer
Gypsyamber D'Souza, Ph.D., Aimee R. Kreimer, Ph.D., Raphael Viscidi, M.D., Michael Pawlita, M.D., Carole Fakhry, M.D., M.P.H., Wayne M. Koch, M.D., William H. Westra, M.D., and Maura L. Gillison, M.D., Ph.D.
Background Substantial molecular evidence suggests a role forhuman papillomavirus (HPV) in the pathogenesis of oropharyngealsquamous-cell carcinoma, but epidemiologic data have been inconsistent.
Methods We performed a hospital-based, case–control studyof 100 patients with newly diagnosed oropharyngeal cancer and200 control patients without cancer to evaluate associationsbetween HPV infection and oropharyngeal cancer. Multivariatelogistic-regression models were used for case–controlcomparisons.
Results A high lifetime number of vaginal-sex partners (26 ormore) was associated with oropharyngeal cancer (odds ratio,3.1; 95% confidence interval [CI], 1.5 to 6.5), as was a highlifetime number of oral-sex partners (6 or more) (odds ratio,3.4; 95% CI, 1.3 to 8.8). The degree of association increasedwith the number of vaginal-sex and oral-sex partners (P valuesfor trend, 0.002 and 0.009, respectively). Oropharyngeal cancerwas significantly associated with oral HPV type 16 (HPV-16)infection (odds ratio, 14.6; 95% CI, 6.3 to 36.6), oral infectionwith any of 37 types of HPV (odds ratio, 12.3; 95% CI, 5.4 to26.4), and seropositivity for the HPV-16 L1 capsid protein (oddsratio, 32.2; 95% CI, 14.6 to 71.3). HPV-16 DNA was detectedin 72% (95% CI, 62 to 81) of 100 paraffin-embedded tumor specimens,and 64% of patients with cancer were seropositive for the HPV-16oncoprotein E6, E7, or both. HPV-16 L1 seropositivity was highlyassociated with oropharyngeal cancer among subjects with a historyof heavy tobacco and alcohol use (odds ratio, 19.4; 95% CI,3.3 to 113.9) and among those without such a history (odds ratio,33.6; 95% CI, 13.3 to 84.8). The association was similarly increasedamong subjects with oral HPV-16 infection, regardless of theirtobacco and alcohol use. By contrast, tobacco and alcohol useincreased the association with oropharyngeal cancer primarilyamong subjects without exposure to HPV-16.
Conclusions Oral HPV infection is strongly associated with oropharyngealcancer among subjects with or without the established risk factorsof tobacco and alcohol use.
Infection with sexually transmitted human papillomavirus (HPV)is a cause of virtually all cervical cancers.1 Molecular evidencealso provides support for a role for HPV, particularly HPV-16,in the pathogenesis of a subgroup of squamous-cell carcinomasof the head and neck.2 Genomic DNA of oncogenic HPV is detectedin approximately 26% of all squamous-cell carcinomas of thehead and neck worldwide,3 but the molecular evidence is mostrigorous and consistent for oropharyngeal squamous-cell carcinoma,in which viral integration and the expression of viral oncogenes(E6 and E7) have been shown.4
The epidemiologic evidence of a causal role for HPV in a subgroupof squamous-cell carcinomas of the head and neck is less rigorousthan the molecular evidence. The example of the relationshipbetween HPV and cervical cancer5 indicates that high-risk sexualbehavior and exposure to and infection with HPV will increasethe risk of other cancers caused by HPV.6 Although each of thesethree factors has been found to increase the risk of squamous-cellcarcinomas of the head and neck,7,8,9,10,11,12,13,14 no singlestudy has shown an association of all three with the developmentof oropharyngeal cancer.
In this study, we focused exclusively on oropharyngeal cancer,for which the molecular evidence of a causal role for HPV iscompelling. Strong epidemiologic data would provide additionalsupport for a causal association between HPV and oropharyngealcancers and might guide future cancer-prevention programs involvingvaccination to prevent oral HPV infection or screening to detectit.
Methods
Patients
Our case–control study was nested within a longitudinalcohort study of patients with newly diagnosed squamous-cellcarcinomas of the head and neck in the outpatient otolaryngologyclinic of the Johns Hopkins Hospital in Baltimore from 2000through 2005. Eligible case patients included those with a confirmeddiagnosis of oropharyngeal squamous-cell carcinoma.
The control group consisted of patients without a history ofcancer who were seen for benign conditions between 2000 and2005 in the same clinic from which the case patients were enrolled(Table 1). Subsequent to enrollment of a case, eligible controlpatients within the same sex and 5-year age categories wereapproached until two control patients were individually matchedto each case patient. The study protocol was approved by theinstitutional review board of the Johns Hopkins Hospital. Written,informed consent was obtained from all patients.
Table 1. Explanatory Variables for Patients with Oropharyngeal Cancer and Control Patients.
Data Collection
Specimens were collected from case patients before therapy andfrom control patients at enrollment. Oral-mucosal specimenswere collected with the use of a saline oral rinse and 5 to10 strokes of a cytology brush (Oral CDx, CDx Laboratories)on the posterior oropharyngeal wall. Serum samples were collectedand stored at –80°C. For case patients, formalin-fixed,paraffin-embedded tumor specimens and, if possible, snap-frozenfresh tumor specimens were obtained for the detection of HPV.
All patients completed an audio, computer-assisted self-administeredinterview that obtained information about demographic characteristics,oral hygiene, medical history, family history of cancer, lifetimesexual behaviors, and lifetime history of marijuana, tobacco,and alcohol use (see the Supplementary Appendix, available withthe full text of this article at www.nejm.org).
Laboratory Studies
In Situ Hybridization for HPV-16 Detection
We looked for HPV-16 in formalin-fixed and paraffin-embeddedtumors from all case subjects, using in situ hybridization–catalyzedsignal amplification for biotinylated probes (Dako GenPoint).15The HPV-16-positive status of a tumor was defined as specificstaining of tumor-cell nuclei for HPV-16.
DNA Purification and Analysis
DNA from oral specimens16 and fresh-frozen tumors17 from a subgroupof case subjects was purified as previously described. The tumorspecimens were microdissected to ensure that more than 70% ofthe sample was DNA from the tumor.
We analyzed purified DNA for 37 types of HPV by means of a multiplexpolymerase-chain-reaction (PCR) assay targeted to the L1 regionof the viral genome, using PGMY09/11 L1 primer pools and primersfor -globin, followed by hybridization to a linear probe array(Roche Molecular Systems).18 The HPV-16 viral load in purifiedDNA from oral-mucosal specimens and fresh-frozen tumor specimenswas determined with the use of a sensitive real-time PCR assaytargeted to the E6 coding region.16,19 The viral load was reportedfor positive samples (those with 1 copy of the virus) and wasadjusted to the total number of human cells tested with theuse of a real-time PCR assay targeted to a single copy of ahuman gene (for endogenous retrovirus 3, ERV3).16
Serologic Analysis
Serum antibodies to the HPV-16 L1 protein were detected withthe use of an enzyme-linked immunosorbent assay (ELISA) basedon virus-like particles.20 Antibodies against HPV-16 E6 andE7 oncoproteins were detected with the use of ELISA and bacteriallyexpressed full-length E6 or E7 as the antigen.21
Statistical Analysis
Cumulative alcohol use was calculated as follows. We defineda drink-equivalent as one 12-oz beer, one 6-oz glass of wine,one 3-oz mixed drink, or one 1.5-oz shot of liquor. The numberof drink-equivalents per week was determined for each patientwithin each 5-year age interval and combined into a measureof lifetime alcohol use, defined as the number of years duringwhich 15 or more drink-equivalents (hereafter called "drinks")per week were consumed.
We calculated cumulative tobacco use in pack-years using informationabout the frequency of use (number of cigarettes, pipes, orcigars smoked per day) and duration of use (during 5-year ageintervals) and accounting for gaps in use. Four cigars or fivepipes per day were deemed equivalent to one pack of cigarettesin the calculation of pack-years.22
Unconditional and conditional multivariate logistic-regressionmodels were used to estimate odds ratios and the associated95% confidence intervals (CIs). Results from the unconditionaland conditional models were similar, and the results from theunconditional models are presented. Final multivariate modelswere created through stepwise elimination of variables of interestfrom univariate analysis while biologically relevant variableswere retained. Owing to the colinearity of sexual behaviors,the effect of each behavior on the risk of cancer was evaluatedin separate multivariate models adjusted for alcohol use, tobaccouse, presence or absence of a family history of head and neckcancer, oral hygiene, age, and sex. To evaluate trends in odds,ordinal variables were modeled as single, continuous, independentvariables. Multiplicative interactions among exposure to HPV,tobacco use, and alcohol use were evaluated by including aninteraction term in the regression model, and statistical significancewas determined with the use of the likelihood-ratio test. Forcomparison of our results with those in previous reports,9,10additive interactions were evaluated with the use of a synergyindex, calculated as (odds ratio for tobacco or alcohol useand HPV–1)÷([odds ratio for tobacco or alcoholuse+odds ratio for HPV]–2).23 The odds ratio for HPV wasfor either seropositivity or infection. Attributable risk wascalculated as previously described.24 P values of less than0.05 for associations were considered to indicate statisticalsignificance. Stata 8.0 software (Stata) was used for all analyses.
Results
We enrolled 130 consecutive patients with newly diagnosed oropharyngealcancer in the longitudinal cohort study from 2000 through 2005,and 100 patients (77%) agreed to participate in our nested case–controlstudy. Case patients who declined enrollment were similar tothose who were enrolled with regard to age, race or ethnic group,and anatomical site of the tumor but were more likely to befemale (P=0.001). Approximately 70% of eligible control patients(200) agreed to participate.
In the univariate analysis, case and control patients were similarwith regard to age, sex, race or ethnic group, and education,but case patients were more likely than control patients tolive outside of Maryland (Table 1). A history of squamous-cellcarcinoma of the head and neck in a first-degree relative, ahistory of cancer in a sibling, a history of oral papillomas,and poor long-term oral hygiene (some or complete tooth lossor infrequent toothbrushing) were all associated with oropharyngealcancer (Table 1). A history of heavy tobacco use (20 pack-yearsor more), a history of heavy alcohol use (15 drinks or moreper week for 15 years or more), and a history of regular marijuanause were also associated with oropharyngeal cancer (Table 1).Similar percentages of case and control patients had no historyof tobacco or alcohol use (13% and 14%, respectively; odds ratio,1.0; 95% CI, 0.5 to 1.9).
Certain kinds of sexual behavior were significantly associatedwith oropharyngeal cancer after adjustment for confounding variables(Table 2). The association with oropharyngeal cancer increasedsignificantly with the number of vaginal-sex partners or oral-sexpartners (P for trend=0.002 and 0.009, respectively) and wasmarkedly elevated among patients with a high lifetime numberof such partners (Table 2).
Table 2. Associations of Oropharyngeal Cancer with Sexual Behaviors.
Oropharyngeal cancer was also strongly associated with serologicmeasures of exposure to HPV-16 and with the presence of oralHPV infection (Table 3). Oropharyngeal cancer was significantlyassociated with seropositivity for the HPV-16 L1 capsid protein,a validated measure of lifetime HPV-16 exposure (odds ratio,32.2; 95% CI, 14.6 to 71.3).25 The presence of an oral HPV-16infection was strongly associated with oropharyngeal cancer(odds ratio, 14.6; 95% CI, 6.3 to 36.6), as was oral infectionwith any of 37 HPV types (odds ratio, 12.3; 95% CI, 5.4 to 26.4)(Table 3).
Table 3. Association of Oropharyngeal Cancer with Exposure to HPV and with Biomarkers of Cancer Associated with HPV-16.
To explore whether the association between sexual behaviorsand oropharyngeal cancer could be explained by HPV-16 exposure,we reevaluated the associations using multivariate models afteradjusting for HPV-16 L1 serologic status. In this analysis,sexual behaviors were no longer significantly associated withoropharyngeal cancer (data not shown). However, associationsof sexual behaviors with oropharyngeal cancer became strongerwhen the analysis was restricted to patients with an HPV-16–positivetumor (Table 2). A high lifetime number of oral-sex or vaginal-sexpartners, engagement in casual sex, early age at first intercourse,and infrequent use of condoms each were associated with HPV-16–positiveoropharyngeal cancer (Table 2).
The association between HPV-16 exposure and oropharyngeal cancerwas investigated among patients with varied use of tobacco andalcohol. The association was greatly increased among patientswithout a history of smoking or drinking who were seropositivefor HPV-16 L1 (odds ratio, 44.8; 95% CI, 5.9 to 338.5) or hadan oral HPV-16 infection (odds ratio, 43.7; 95% CI, 4.2 to 452.7).HPV-16 L1 seropositivity and oral HPV-16 infection were alsohighly associated with oropharyngeal cancer among patients witha history of heavy tobacco and alcohol use and those withoutsuch a history (Table 4). Thus, measures of both lifetime andprevalent oral HPV-16 infection were associated with an increasedrisk of oropharyngeal cancer, whether or not there was a historyof use of tobacco, alcohol, or both.
Table 4. Odds Ratios for Associations of Oropharyngeal Cancer with Tobacco Use, Alcohol Use, Seropositivity for HPV-16, and Oral Infection with HPV-16.
We evaluated whether combined exposure to HPV and tobacco oralcohol further increased the odds that oropharyngeal cancerwould develop. No evidence of synergy was found (Table 4, top):combined exposure to HPV and heavy tobacco and alcohol use wasnot additive (synergy index <1). Moreover, when the analysiswas restricted to patients who were seropositive for the HPV-16L1 protein, the odds of oropharyngeal cancer were not increasedamong heavy users of tobacco or alcohol (Table 4, bottom). Bycontrast, among patients who were seronegative for the HPV-16L1 protein, the odds of oropharyngeal cancer were increasedamong heavy users of tobacco or alcohol, and the odds of oropharyngealcancer were further increased among heavy users of both tobaccoand alcohol (synergy index >1) (Table 4, bottom). Similarrelationships were observed in patients with and those withoutthe presence of an oral HPV-16 infection (Table 4). Therefore,tobacco and alcohol were important risk factors for oropharyngealcancer, but they may not have acted as cofactors in HPV-mediatedcarcinogenesis in the oropharynx.
In the multivariate analysis, oropharyngeal cancer was independentlyassociated with HPV-16 L1 seropositivity (odds ratio, 32.2;95% CI, 14.6 to 71.3), poor dentition (odds ratio, 4.1; 95%CI, 1.6 to 10.6), infrequent toothbrushing (odds ratio, 6.9;95% CI, 1.6 to 30.3), history of squamous-cell carcinomas ofthe head and neck in a first-degree family member (odds ratio,5.4; 95% CI, 1.0 to 30.8), and heavy tobacco use (odds ratio,2.5; 95% CI, 1.1 to 6.0) after adjustment for age, sex, andalcohol use. These factors were collectively estimated to beresponsible for 90% of cases of oropharyngeal cancers (the attributablerisk; 95% CI, 72 to 96), with 55% of cases (95% CI, 45 to 63)attributable to HPV-16 exposure alone.
The percentage of oropharyngeal cancers in which HPV-16 genomicDNA was detected by in situ hybridization was 72% (95% CI, 62to 81) (Table 3 and Figure 1). Of the 60 specimens of availablefresh-frozen tumor, 35 (58%; 95% CI, 45 to 71) were positivefor HPV-16, with a median of 1.2 viral copies per cell (interquartilerange, 0.02 to 11) analyzed. Five fresh-frozen specimens werepositive for a high-risk type of HPV other than HPV-16 (twofor HPV-33, one for HPV-35, and two for both HPV-33 and HPV-16).
Figure 1. Representative Case of Oropharyngeal Squamous-Cell Carcinoma That Was Positive for HPV-16 on In Situ Hybridization.
Panel A shows fronds of in situ carcinoma, and Panel C shows nests of deeply invasive tonsillar carcinoma (both panels, hematoxylin and eosin). HPV-16 is visualized as hybridization signals (brown dots) within the tumor-cell nuclei in the corresponding right-hand images (Panels B and D, respectively).
To corroborate the in situ data, we tested for serum antibodiesagainst HPV-16 oncoprotein E6, E7, or both, which have highspecificity but moderate sensitivity for the detection of invasivecancer associated with HPV-16.26 Such antibodies were foundin 64% of the case patients and in 4% of the control patients(odds ratio, 58.4; 95% CI, 24.2 to 138.3; P<0.001) (Table 2).
Discussion
This epidemiologic study provides support for the associationbetween HPV and a subgroup of oropharyngeal cancers. The strengthof the evidence is underscored by the associations of high-risksexual behaviors, oral HPV infection, and HPV-16 exposure (asdetermined from the results of serologic tests) with oropharyngealcancer. Furthermore, we found that HPV-16 DNA was specificallylocalized to tumor-cell nuclei in 72% of 100 paraffin-embeddedspecimens of oropharyngeal cancers, a finding corroborated bythe high prevalence of antibodies for HPV-16 oncoprotein E6,E7, or both (64%) in the patients with oropharyngeal cancer.Although a cause-and-effect relationship cannot be inferredfrom a single study, our findings confirm and extend those ofother case–control studies.7,8,9,10,11,12,13,14 Our resultsare also consistent with a previous report of an increase inthe subsequent risk of oropharyngeal cancer by a factor of 14among HPV-16 L1 seropositive subjects,26 which provides strongevidence that exposure to HPV can precede the appearance oforopharyngeal cancer by 10 years or more.
The degree to which oral HPV infection may interact with tobaccouse, alcohol use, or both to increase the risk of squamous-cellcarcinomas of the head and neck has been unclear. A greater-than-additiverisk has been reported, albeit inconsistently,8,9,10 for patientsexposed to both HPV and tobacco9 and those exposed to both HPVand alcohol.10 We found that exposure to HPV increased the associationwith oropharyngeal cancer regardless of tobacco and alcoholuse, but we uncovered no evidence of synergy between exposureto HPV and tobacco or alcohol use. For these reasons, our datasuggest two distinct pathways for the development of oropharyngealcancer: one driven predominantly by the carcinogenic effectsof tobacco or alcohol (or both) and another by HPV-induced genomicinstability.
Our data suggest that oral HPV infection is sexually acquired.Oral–genital contact was strongly associated with oropharyngealcancer, but we cannot rule out transmission through direct mouth-to-mouthcontact or other means. Certain sexual behaviors13,14 and ahistory of oral HPV infection7,10 were associated with an increasedrisk of squamous-cell carcinomas of the head and neck in previousstudies in which 25% or more of the tumors from patients werepositive for HPV DNA but not those in which less than 25% ofthe tumors from patients were positive for HPV DNA.8,9 Discrepantfindings may be explained by the heterogeneity of the case populations,with variable percentages of cancer cases attributable primarilyto tobacco and alcohol use, as compared with HPV infection.In our study, the heterogeneity of case patients was minimizedby restricting enrollment to patients with oropharyngeal cancer,90% of whom had tumors on the tonsil or base of the tongue.
Although HPV-16 alone accounts for more than 90% of cases ofHPV-positive squamous-cell carcinomas of the head and neck,8a more accurate and probably higher proportion might be foundby testing for other types of HPV (e.g., types 18, 31, 33, and35), which are infrequently detected in oropharyngeal cancers.
In our study, oropharyngeal cancer was independently associatedwith a family history of squamous-cell carcinoma of the headand neck and poor oral hygiene, findings that are consistentwith other reports.27 The risk of cervical cancer is also increasedin women with a family history of that cancer.28,29 Until specificgenetic markers for the risk of an HPV-associated cancer areidentified, familial aggregation due to shared environmentalexposures cannot be ruled out as an explanation for these findings.Poor dentition,30,31 infrequent toothbrushing,31,32 and infrequentdental visits30,33 have been associated with an increased riskof squamous-cell carcinomas of the head and neck. Because toothloss is commonly caused by chronic bacterial infections (e.g.,periodontitis), it may serve as a surrogate for chronic infectionand inflammation, which may be important in the pathogenesisof cancer. Particular coinfections in the cervix (e.g., infectionwith Chlamydia trachomatis) increase the risk of cancer,34 andour results suggest that bacterial coinfections could play asimilar role in the oral region. The absence of data on diet,which is associated with the risk of squamous-cell carcinomasof the head and neck,35 is a limitation of our study but isunlikely to explain the observed associations with HPV infection.
The public health implications of our findings are underscoredby the annual increases in the incidence of tonsillar and base-of-tonguecancers in the United States since 1973.36,37 The widespreadoral sexual practices among adolescents may be a contributingfactor in this increase.38 Our results and those of other studiesprovide a rationale for HPV vaccination in both boys and girls— since oropharyngeal cancers occur in men and women.If vaccination is as effective in preventing oral HPV-16 infectionas it is in preventing cervical infection,39 a substantial reductionin the incidence of oropharyngeal cancer in vaccinated populationswould provide the ultimate evidence of causality.
Supported in part by grants from the Damon Runyon Cancer ResearchFoundation (Clinical Investigator Award, to Dr. Gillison), theState of Maryland Cigarette Restitution Fund (to Dr. Gillison),the National Institute of Dental and Craniofacial Research (DE016631-01,to Dr. Gillison), and the National Institutes of Health (TrainingGrant T32AI50056, to Dr. D'Souza).
No potential conflict of interest relevant to this article wasreported.
We thank Janell Alden, Nicole Benoit, Barbara Clayman, ErlindaEmbuscado, Eleni Goshu, Megan Hyle, Zubair Khan, Katherine Locke,Elizabeth O'Leary, Catherine Pevtsova, Carolyn Plescia, andWeihong Xiao for their roles in data collection and laboratoryanalysis; Dr. Shanaz Begum for technical expertise; Dr. ElizabethGarrett-Mayer for statistical advice; and Dr. David E. Symerfor comments on the manuscript.
Source Information
From the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health (G.D.); the Departments of Pediatrics (R.V.), Otolaryngology–Head and Neck Surgery (C.F., W.M.K.), and Pathology (W.H.W.), Johns Hopkins Hospital; and the Division of Viral Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University (M.L.G.) — all in Baltimore; the Division of Cancer Prevention, National Cancer Institute, Bethesda, MD (A.R.K.); and the Infection and Cancer Control Program, German Cancer Research Center, Heidelberg, Germany (M.P.).
Address reprint requests to Dr. Gillison at Johns Hopkins University, Cancer Research Bldg. I, Rm. 3M 54A, 1650 Orleans St., Baltimore, MD 21231, or to gillima{at}jhmi.edu.
References
Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-19. [CrossRef][ISI][Medline]
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;92:709-720. [Free Full Text]
Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467-475. [Free Full Text]
Gillison ML. Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin Oncol 2004;31:744-754. [CrossRef][ISI][Medline]
Bosch FX, De Sanjose S. Human papillomavirus and cervical cancer -- burden and assessment of causality. J Natl Cancer Inst Monogr 2003;31:3-13. [Free Full Text]
Gillison ML, Shah KV. Role of mucosal human papillomavirus in nongenital cancers. J Natl Cancer Inst Monogr 2003;31:57-65. [Free Full Text]
Hansson BG, Rosenquist K, Antonsson A, et al. Strong association between infection with human papillomavirus and oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Acta Otolaryngol (Stockh) 2005;125:1337-1344. [CrossRef][Medline]
Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003;95:1772-1783. [Free Full Text]
Schwartz SM, Daling JR, Doody DR, et al. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 1998;90:1626-1636. [Free Full Text]
Smith EM, Ritchie JM, Summersgill KF, et al. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst 2004;96:449-455. [Free Full Text]
Dahlstrom KR, Adler-Storthz K, Etzel CJ, et al. Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers: a matched pair analysis. Clin Cancer Res 2003;9:2620-2626. [Free Full Text]
Maden C, Beckmann AM, Thomas DB, et al. Human papillomaviruses, herpes simplex viruses, and the risk of oral cancer in men. Am J Epidemiol 1992;135:1093-1102. [Free Full Text]
Smith EM, Ritchie JM, Summersgill KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004;108:766-772. [CrossRef][ISI][Medline]
Rosenquist K, Wennerberg J, Schildt EB, Bladstrom A, Goran Hansson B, Andersson G. Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Acta Otolaryngol (Stockh) 2005;125:1327-1336. [CrossRef][Medline]
Huang CC, Qiu JT, Kashima ML, Kurman RJ, Wu TC. Generation of type-specific probes for the detection of single-copy human papillomavirus by a novel in situ hybridization method. Mod Pathol 1998;11:971-977. [ISI][Medline]
D'Souza G, Sugar E, Ruby W, Gravitt P, Gillison M. Analysis of the effect of DNA purification on detection of human papillomavirus in oral rinse samples by PCR. J Clin Microbiol 2005;43:5526-5535. [Free Full Text]
Fearon ER, Feinberg AP, Hamilton SH, Vogelstein B. Loss of genes on the short arm of chromosome 11 in bladder cancer. Nature 1985;318:377-380. [CrossRef][Medline]
Peyton CL, Gravitt PE, Hunt WC, et al. Determinants of genital human papillomavirus detection in a US population. J Infect Dis 2001;183:1554-1564. [CrossRef][ISI][Medline]
Gravitt PE, Peyton C, Wheeler C, Apple R, Higuchi R, Shah KV. Reproducibility of HPV 16 and HPV 18 viral load quantitation using TaqMan real-time PCR assays. J Virol Methods 2003;112:23-33. [CrossRef][ISI][Medline]
Viscidi RP, Ahdieh-Grant L, Clayman B, et al. Serum immunoglobulin G response to human papillomavirus type 16 virus-like particles in human immunodeficiency virus (HIV)-positive and risk-matched HIV-negative women. J Infect Dis 2003;187:194-205. [CrossRef][ISI][Medline]
Sehr P, Zumbach K, Pawlita M. A generic capture ELISA for recombinant proteins fused to glutathione S-transferase: validation for HPV serology. J Immunol Methods 2001;253:153-162. [CrossRef][ISI][Medline]
Benhamou S, Benhamou E, Flamant R. Lung cancer risk associated with cigar and pipe smoking. Int J Cancer 1986;37:825-829. [ISI][Medline]
Hosmer DW, Lemeshow S. Confidence interval estimation of interaction. Epidemiology 1992;3:452-456. [ISI][Medline]
Greenland S, Drescher K. Maximum likelihood estimation of the attributable fraction from logistic models. Biometrics 1993;49:865-872. [CrossRef][ISI][Medline]
Dillner J. The serological response to papillomaviruses. Semin Cancer Biol 1999;9:423-430. [CrossRef][ISI][Medline]
Mork J, Lie AK, Glattre E, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001;344:1125-1131. [Free Full Text]
Brown LM, Gridley G, Diehl SR, et al. Family cancer history and susceptibility to oral carcinoma in Puerto Rico. Cancer 2001;92:2102-2108. [CrossRef][ISI][Medline]
Hemminki K, Li X, Mutanen P. Familial risks in invasive and in situ cervical cancer by histological type. Eur J Cancer Prev 2001;10:83-89. [CrossRef][ISI][Medline]
Zelmanowicz Ade M, Schiffman M, Herrero R, et al. Family history as a co-factor for adenocarcinoma and squamous cell carcinoma of the uterine cervix: results from two studies conducted in Costa Rica and the United States. Int J Cancer 2005;116:599-605. [CrossRef][ISI][Medline]
Bundgaard T, Wildt J, Frydenberg M, Elbrond O, Nielsen JE. Case-control study of squamous cell cancer of the oral cavity in Denmark. Cancer Causes Control 1995;6:57-67. [CrossRef][ISI][Medline]
Zheng TZ, Boyle P, Hu HF, et al. Dentition, oral hygiene, and risk of oral cancer: a case-control study in Beijing, People's Republic of China. Cancer Causes Control 1990;1:235-241. [CrossRef][ISI][Medline]
Moreno-Lopez LA, Esparza-Gomez GC, Gonzalez-Navarro A, Cerero-Lapiedra R, Gonzalez-Hernandez MJ, Dominguez-Rojas V. Risk of oral cancer associated with tobacco smoking, alcohol consumption and oral hygiene: a case-control study in Madrid, Spain. Oral Oncol 2000;36:170-174. [CrossRef][ISI][Medline]
Maier H, Zoller J, Herrmann A, Kreiss M, Heller WD. Dental status and oral hygiene in patients with head and neck cancer. Otolaryngol Head Neck Surg 1993;108:655-661. [ISI][Medline]
Smith JS, Bosetti C, Munoz N, et al. Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case-control study. Int J Cancer 2004;111:431-439. [CrossRef][ISI][Medline]
Kreimer AR, Randi G, Herrero R, Castellsague X, La Vecchia C, Franceschi S. Diet and body mass, and oral and oropharyngeal squamous cell carcinomas: analysis from the IARC multinational case-control study. Int J Cancer 2006;118:2293-2297. [CrossRef][ISI][Medline]
Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer 2005;103:1843-1849. [CrossRef][ISI][Medline]
Frisch M, Hjalgrim H, Jaeger AB, Biggar RJ. Changing patterns of tonsillar squamous cell carcinoma in the United States. Cancer Causes Control 2000;11:489-495. [CrossRef][ISI][Medline]
Mosher WD, Chandra A, Jones J. Sexual behavior and selected health measures: men and women 15-44 years of age, United States, 2002. Adv Data 2005;362:1-55. [Medline]
Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247-1255. [CrossRef][ISI][Medline]
Human Papillomavirus and Oropharyngeal Cancer
Ukpo O. C., Moore E. J., Smith D. I., Williams H., Higgins C. D., Crawford D. H., Braakhuis B. J., Snijders P. J., Leemans C. R., Gillison M. L.
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(2009). The EVER Proteins as a Natural Barrier against Papillomaviruses: a New Insight into the Pathogenesis of Human Papillomavirus Infections. Microbiol. Mol. Biol. Rev.
73: 348-370
[Abstract][Full Text]
Ernster, J. A., Sciotto, C. G., O'Brien, M. M., Robinson, L. J., Willson, T.
(2009). Prevalence of Oncogenic Human Papillomavirus 16 and 18 in the Palatine Tonsils of the General Adult Population. Arch Otolaryngol Head Neck Surg
135: 554-557
[Abstract][Full Text]
Lippman, S. M.
(2009). Cancer Prevention Research: Back to the Future. Cancer Prevention Research
2: 503-513
[Full Text]
Berthiller, J., Lee, Y.-c. A., Boffetta, P., Wei, Q., Sturgis, E. M., Greenland, S., Morgenstern, H., Zhang, Z.-F., Lazarus, P., Muscat, J., Chen, C., Schwartz, S. M., Eluf Neto, J., Wunsch Filho, V., Koifman, S., Curado, M. P., Matos, E., Fernandez, L., Menezes, A., Daudt, A. W., Ferro, G., Brennan, P., Hashibe, M.
(2009). Marijuana Smoking and the Risk of Head and Neck Cancer: Pooled Analysis in the INHANCE Consortium. Cancer Epidemiol. Biomarkers Prev.
18: 1544-1551
[Abstract][Full Text]
JO, S., JUHASZ, A., ZHANG, K., RUEL, C., LOERA, S., WILCZYNSKI, S. P., YEN, Y., LIU, X., ELLENHORN, J., LIM, D., PAZ, B., SOMLO, G., VORA, N., SHIBATA, S.
(2009). Human Papillomavirus Infection as a Prognostic Factor in Oropharyngeal Squamous Cell Carcinomas Treated in a Prospective Phase II Clinical Trial. Anticancer Res
29: 1467-1474
[Abstract][Full Text]
Applebaum, E., Ruhlen, T. N., Kronenberg, F. R., Hayes, C., Peters, E. S.
(2009). Oral Cancer Knowledge, Attitudes and Practices: A Survey of Dentists and Primary Care Physicians in Massachusetts. Journal of the American Dental Association
140: 461-467
[Abstract][Full Text]
Hennessey, P.T., Westra, W.H., Califano, J.A.
(2009). Human Papillomavirus and Head and Neck Squamous Cell Carcinoma: Recent Evidence and Clinical Implications. JDR
88: 300-306
[Abstract][Full Text]
Conway, M.J., Meyers, C.
(2009). Replication and Assembly of Human Papillomaviruses. JDR
88: 307-317
[Abstract][Full Text]
Kiyota, N., Tahara, M., Kadowaki, S., Fuse, N., Doi, T., Minami, H., Ohtsu, A.
(2009). Systemic Chemotherapy with Cisplatin Plus 5-FU (PF) for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M SCCHN): Efficacy and Safety of a Lower Dose of PF (80/800) at a Single Institution in Japan. Jpn J Clin Oncol
39: 225-230
[Abstract][Full Text]
Cook, M. B., Dawsey, S. M., Freedman, N. D., Inskip, P. D., Wichner, S. M., Quraishi, S. M., Devesa, S. S., McGlynn, K. A.
(2009). Sex Disparities in Cancer Incidence by Period and Age. Cancer Epidemiol. Biomarkers Prev.
18: 1174-1182
[Abstract][Full Text]
Wolf, G. T.
(2009). Tradition, Teamwork, and Tailored Treatment: Surgical Oncology in the Genomic Era. Arch Otolaryngol Head Neck Surg
135: 337-341
[Full Text]
Tezal, M., Sullivan Nasca, M., Stoler, D. L., Melendy, T., Hyland, A., Smaldino, P. J., Rigual, N. R., Loree, T. R.
(2009). Chronic Periodontitis-Human Papillomavirus Synergy in Base of Tongue Cancers. Arch Otolaryngol Head Neck Surg
135: 391-396
[Abstract][Full Text]
Sikora, A. G., Morris, L. G., Sturgis, E. M.
(2009). Bidirectional Association of Anogenital and Oral Cavity/Pharyngeal Carcinomas in Men. Arch Otolaryngol Head Neck Surg
135: 402-405
[Abstract][Full Text]
Grose, C.
(2009). Bandicoots, Bonobos, and Boys: Papillomavirus and Vaccination Strategies. Pediatrics
123: 1244-1245
[Full Text]
Savani, B. N., Goodman, S., Barrett, A. J.
(2009). Can Routine Posttransplant HPV Vaccination Prevent Commonly Occurring Epithelial Cancers after Allogeneic Stem Cell Transplantation?. Clin. Cancer Res.
15: 2219-2221
[Abstract][Full Text]
Rampias, T., Sasaki, C., Weinberger, P., Psyrri, A.
(2009). E6 and E7 Gene Silencing and Transformed Phenotype of Human Papillomavirus 16-Positive Oropharyngeal Cancer Cells. JNCI J Natl Cancer Inst
101: 412-423
[Abstract][Full Text]
Porras, C., Rodriguez, A. C., Hildesheim, A., Herrero, R., Gonzalez, P., Wacholder, S., Burk, R. D., Schiffman, M.
(2009). Human Papillomavirus Types by Age in Cervical Cancer Precursors: Predominance of Human Papillomavirus 16 in Young Women. Cancer Epidemiol. Biomarkers Prev.
18: 863-865
[Abstract][Full Text]
Furniss, C. S., McClean, M. D., Smith, J. F., Bryan, J., Applebaum, K. M., Nelson, H. H., Posner, M. R., Kelsey, K. T.
(2009). Human papillomavirus 6 seropositivity is associated with risk of head and neck squamous cell carcinoma, independent of tobacco and alcohol use. Ann Oncol
20: 534-541
[Abstract][Full Text]
Klussmann, J. P., Mooren, J. J., Lehnen, M., Claessen, S. M.H., Stenner, M., Huebbers, C. U., Weissenborn, S. J., Wedemeyer, I., Preuss, S. F., Straetmans, J. M.J.A.A., Manni, J. J., Hopman, A. H.N., Speel, E.-J. M.
(2009). Genetic Signatures of HPV-related and Unrelated Oropharyngeal Carcinoma and Their Prognostic Implications. Clin. Cancer Res.
15: 1779-1786
[Abstract][Full Text]
Michaud, W. A., Nichols, A. C., Mroz, E. A., Faquin, W. C., Clark, J. R., Begum, S., Westra, W. H., Wada, H., Busse, P. M., Ellisen, L. W., Rocco, J. W.
(2009). Bcl-2 Blocks Cisplatin-Induced Apoptosis and Predicts Poor Outcome Following Chemoradiation Treatment in Advanced Oropharyngeal Squamous Cell Carcinoma. Clin. Cancer Res.
15: 1645-1654
[Abstract][Full Text]
Hashibe, M., Brennan, P., Chuang, S.-c., Boccia, S., Castellsague, X., Chen, C., Curado, M. P., Dal Maso, L., Daudt, A. W., Fabianova, E., Fernandez, L., Wunsch-Filho, V., Franceschi, S., Hayes, R. B., Herrero, R., Kelsey, K., Koifman, S., La Vecchia, C., Lazarus, P., Levi, F., Lence, J. J., Mates, D., Matos, E., Menezes, A., McClean, M. D., Muscat, J., Eluf-Neto, J., Olshan, A. F., Purdue, M., Rudnai, P., Schwartz, S. M., Smith, E., Sturgis, E. M., Szeszenia-Dabrowska, N., Talamini, R., Wei, Q., Winn, D. M., Shangina, O., Pilarska, A., Zhang, Z.-F., Ferro, G., Berthiller, J., Boffetta, P.
(2009). Interaction between Tobacco and Alcohol Use and the Risk of Head and Neck Cancer: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol. Biomarkers Prev.
18: 541-550
[Abstract][Full Text]
Lohavanichbutr, P., Houck, J., Fan, W., Yueh, B., Mendez, E., Futran, N., Doody, D. R., Upton, M. P., Farwell, D. G., Schwartz, S. M., Zhao, L. P., Chen, C.
(2009). Genomewide Gene Expression Profiles of HPV-Positive and HPV-Negative Oropharyngeal Cancer: Potential Implications for Treatment Choices. Arch Otolaryngol Head Neck Surg
135: 180-188
[Abstract][Full Text]
Dickson, N. P., Ryding, J., van Roode, T., Paul, C., Herbison, P., Dillner, J., Skegg, D. C.G.
(2009). Male Circumcision and Serologically Determined Human Papillomavirus Infection in a Birth Cohort. Cancer Epidemiol. Biomarkers Prev.
18: 177-183
[Abstract][Full Text]
Ferris, D. G., Waller, J. L., Miller, J., Patel, P., Price, G. A., Jackson, L., Wilson, C.
(2009). Variables Associated With Human Papillomavirus (HPV) Vaccine Acceptance by Men. J Am Board Fam Med
22: 34-42
[Abstract][Full Text]
Meyer, M. S., Applebaum, K. M., Furniss, C. S., Peters, E. S., Luckett, B. G., Smith, J. F., Bryan, J., McClean, M. D., Marsit, C., Kelsey, K. T.
(2008). Human Papillomavirus-16 Modifies the Association between Fruit Consumption and Head and Neck Squamous Cell Carcinoma. Cancer Epidemiol. Biomarkers Prev.
17: 3419-3426
[Abstract][Full Text]
Chaiyachati, K., Cinti, S. K., Kauffman, C. A., Riddell, J.
(2008). HIV-Infected Patients With Anal Carcinoma Who Subsequently Developed Oral Squamous Cell Carcinoma: Report of 2 Cases. J Int Assoc Physicians AIDS Care (Chic Ill)
7: 306-310
[Abstract]
Stanley, M.
(2008). HPV vaccines: are they the answer?. Br Med Bull
88: 59-74
[Abstract][Full Text]
van Zeeburg, H. J. T., Snijders, P. J. F., Wu, T., Gluckman, E., Soulier, J., Surralles, J., Castella, M., van der Wal, J. E., Wennerberg, J., Califano, J., Velleuer, E., Dietrich, R., Ebell, W., Bloemena, E., Joenje, H., Leemans, C. R., Brakenhoff, R. H.
(2008). Clinical and Molecular Characteristics of Squamous Cell Carcinomas From Fanconi Anemia Patients. JNCI J Natl Cancer Inst
100: 1649-1653
[Abstract][Full Text]
Burnett-Hartman, A. N., Newcomb, P. A., Potter, J. D.
(2008). Infectious Agents and Colorectal Cancer: A Review of Helicobacter pylori, Streptococcus bovis, JC Virus, and Human Papillomavirus. Cancer Epidemiol. Biomarkers Prev.
17: 2970-2979
[Abstract][Full Text]
Sok, J. C., Grandis, J. R.
(2008). Genetic Screening for Oral Human Papillomavirus Infections and Cancers of the Head and Neck. Clin. Cancer Res.
14: 6723-6724
[Abstract][Full Text]
Agrawal, Y., Koch, W. M., Xiao, W., Westra, W. H., Trivett, A. L., Symer, D. E., Gillison, M. L.
(2008). Oral Human Papillomavirus Infection Before and After Treatment for Human Papillomavirus 16-Positive and Human Papillomavirus 16-Negative Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res.
14: 7143-7150
[Abstract][Full Text]
Tungteakkhun, S. S., Filippova, M., Neidigh, J. W., Fodor, N., Duerksen-Hughes, P. J.
(2008). The Interaction between Human Papillomavirus Type 16 and FADD Is Mediated by a Novel E6 Binding Domain. J. Virol.
82: 9600-9614
[Abstract][Full Text]
Haddad, R. I., Shin, D. M.
(2008). Recent Advances in Head and Neck Cancer. NEJM
359: 1143-1154
[Full Text]
Worden, F. P., Kumar, B., Lee, J. S., Wolf, G. T., Cordell, K. G., Taylor, J. M.G., Urba, S. G., Eisbruch, A., Teknos, T. N., Chepeha, D. B., Prince, M. E., Tsien, C. I., D'Silva, N. J., Yang, K., Kurnit, D. M., Mason, H. L., Miller, T. H., Wallace, N. E., Bradford, C. R., Carey, T. E.
(2008). Chemoselection As a Strategy for Organ Preservation in Advanced Oropharynx Cancer: Response and Survival Positively Associated With HPV16 Copy Number. JCO
26: 3138-3146
[Abstract][Full Text]
Singh, B., Pfister, D. G.
(2008). Individualized Treatment Selection in Patients With Head and Neck Cancer: Do Molecular Markers Meet the Challenge?. JCO
26: 3114-3116
[Full Text]
Huang, C. M.
(2008). Human Papillomavirus and Vaccination. Mayo Clin Proc.
83: 701-707
[Abstract][Full Text]
Goldstein, N. E., Genden, E., Morrison, R. S.
(2008). Palliative Care for Patients With Head and Neck Cancer: "I Would Like a Quick Return to a Normal Lifestyle". JAMA
299: 1818-1825
[Abstract][Full Text]
Hughes, D S, Powell, N, Fiander, A N
(2008). Will vaccination against human papillomavirus prevent eye disease? A review of the evidence. Br. J. Ophthalmol.
92: 460-465
[Abstract][Full Text]
Marur, S., Forastiere, A. A.
(2008). Head and Neck Cancer: Changing Epidemiology, Diagnosis, and Treatment. Mayo Clin Proc.
83: 489-501
[Abstract][Full Text]
Gillison, M. L., D'Souza, G., Westra, W., Sugar, E., Xiao, W., Begum, S., Viscidi, R.
(2008). Distinct Risk Factor Profiles for Human Papillomavirus Type 16-Positive and Human Papillomavirus Type 16-Negative Head and Neck Cancers. JNCI J Natl Cancer Inst
100: 407-420
[Abstract][Full Text]
Sanchez, I. E., Dellarole, M., Gaston, K., de Prat Gay, G.
(2008). Comprehensive comparison of the interaction of the E2 master regulator with its cognate target DNA sites in 73 human papillomavirus types by sequence statistics. Nucleic Acids Res
36: 756-769
[Abstract][Full Text]
Chaturvedi, A. K., Engels, E. A., Anderson, W. F., Gillison, M. L.
(2008). Incidence Trends for Human Papillomavirus-Related and -Unrelated Oral Squamous Cell Carcinomas in the United States. JCO
26: 612-619
[Abstract][Full Text]
Goon, P, Sonnex, C
(2008). Frequently asked questions about genital warts in the genitourinary medicine clinic: an update and review of recent literature. Sex. Transm. Infect.
84: 3-7
[Abstract][Full Text]
Gralow, J., Ozols, R. F., Bajorin, D. F., Cheson, B. D., Sandler, H. M., Winer, E. P., Bonner, J., Demetri, G. D., Curran, W. Jr, Ganz, P. A., Kramer, B. S., Kris, M. G., Markman, M., Mayer, R. J., Raghavan, D., Ramsey, S., Reaman, G. H., Sawaya, R., Schuchter, L. M., Sweetenham, J. W., Vahdat, L. T., Davidson, N. E., Schilsky, R. L., Lichter, A. S.
(2008). Clinical Cancer Advances 2007: Major Research Advances in Cancer Treatment, Prevention, and Screening--A Report From the American Society of Clinical Oncology. JCO
26: 313-325
[Abstract][Full Text]
Ignatius, R. T., Wills, S. M., Nadeau, L., Deperalta-Venturina, M., Weiner, S.
(2008). Leptomeningeal Carcinomatosis Due to Squamous Cell Carcinoma of the Uterine Cervix Associated With HPV-45. JCO
26: 154-156
[Full Text]
Choong, N., Vokes, E.
(2008). Expanding Role of the Medical Oncologist in the Management of Head and Neck Cancer. CA Cancer J Clin
58: 32-53
[Abstract][Full Text]
Applebaum, K. M., Furniss, C. S., Zeka, A., Posner, M. R., Smith, J. F., Bryan, J., Eisen, E. A., Peters, E. S., McClean, M. D., Kelsey, K. T.
(2007). Lack of Association of Alcohol and Tobacco with HPV16-Associated Head and Neck Cancer. JNCI J Natl Cancer Inst
99: 1801-1810
[Abstract][Full Text]
Friedman, J., Nottingham, L., Duggal, P., Pernas, F. G., Yan, B., Yang, X. P., Chen, Z., Van Waes, C.
(2007). Deficient TP53 Expression, Function, and Cisplatin Sensitivity Are Restored by Quinacrine in Head and Neck Cancer. Clin. Cancer Res.
13: 6568-6578
[Abstract][Full Text]
Hoque, A., Parnes, H. L., Stefanek, M. E., Heymach, J. V., Brown, P. H., Lippman, S. M.
(2007). Meeting Report: Fifth Annual AACR Frontiers in Cancer Prevention Research. Cancer Res.
67: 8989-8993
[Abstract][Full Text]
Smith, J. L., Campos, S. K., Ozbun, M. A.
(2007). Human Papillomavirus Type 31 Uses a Caveolin 1- and Dynamin 2-Mediated Entry Pathway for Infection of Human Keratinocytes. J. Virol.
81: 9922-9931
[Abstract][Full Text]
Ukpo, O. C., Moore, E. J., Smith, D. I., Williams, H., Higgins, C. D., Crawford, D. H., Braakhuis, B. J., Snijders, P. J., Leemans, C. R., Gillison, M. L.
(2007). Human Papillomavirus and Oropharyngeal Cancer. NEJM
357: 1156-1158
[Full Text]
Glick, M.
(2007). The health questionnaire: A continually changing component of practice. Journal of the American Dental Association
138: 932-934
[Full Text]
Baden, L. R., Curfman, G. D., Morrissey, S., Drazen, J. M.
(2007). Human Papillomavirus Vaccine -- Opportunity and Challenge. NEJM
356: 1990-1991
[Full Text]
Syrjanen, S.
(2007). Human Papillomaviruses in Head and Neck Carcinomas. NEJM
356: 1993-1995
[Full Text]
-globin, followed by hybridization to a linear probe array (Roche Molecular Systems).18 The HPV-16 viral load in purified DNA from oral-mucosal specimens and fresh-frozen tumor specimens was determined with the use of a sensitive real-time PCR assay targeted to the E6 coding region.16,19 The viral load was reported for positive samples (those with 
1 copy of the virus) and was adjusted to the total number of human cells tested with the use of a real-time PCR assay targeted to a single copy of a human gene (for endogenous retrovirus 3, ERV3).16 
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