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Purpose The incidence of human papilloma virus (HPV)–positive oropharyngeal cancers has risen rapidly in recent decades among men in the United States. We investigated the US population–level effect of prophylactic HPV vaccination on the burden of oral HPV infection, the principal cause of HPV-positive oropharyngeal cancers. Methods We conducted a cross-sectional study of men and women 18 to 33 years of age (N = 2,627) within the National Health and Nutrition Examination Survey 2011 to 2014, a representative sample of the US population. Oral HPV infection with vaccine types 16, 18, 6, or 11 was compared by HPV vaccination status, as measured by self-reported receipt of at least one dose of the HPV vaccine. Analyses accounted for the complex sampling design and were adjusted for age, sex, and race. Statistical significance was assessed using a quasi-score test. Results Between 2011 and 2014, 18.3% of the US population 18 to 33 years of age reported receipt of at least one dose of the HPV vaccine before the age of 26 years (29.2% in women and 6.9% in men; P < .001). The prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated individuals (0.11% v 1.61%; Padj = .008), corresponding to an estimated 88.2% (95% CI, 5.7% to 98.5%) reduction in prevalence after model adjustment for age, sex, and race. Notably, the prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated men (0.0% v 2.13%; Padj = .007). Accounting for vaccine uptake, the population-level effect of HPV vaccination on the burden of oral HPV16/18/6/11 infections was 17.0% overall, 25.0% in women, and 6.9% in men. Conclusion HPV vaccination was associated with reduction in vaccine-type oral HPV prevalence among young US adults. However, because of low vaccine uptake, the population-level effect was modest overall and particularly low in men.

BACKGROUND Sexual behavior and oral human papillomavirus (HPV) infection are risk factors for oral squamous cell carcinoma (OSCC). The effects of OSCC diagnosis and treatment on subsequent relationship stress and sexual behavior are unknown. METHODS Incident cases of HPV-positive or HPV-negative OSCC in patients who had a partnered relationship and partners of patients with oropharyngeal cancer were eligible for a study in which surveys were administered at diagnosis and at the 6-month follow-up time point to assess relationship distress, HPV transmission and concerns about health consequences, and sexual behavior. The frequency distributions of responses, stratified by tumor HPV status, were compared at baseline and follow-up. RESULTS In total, 262 patients with OSCC and 81 partners were enrolled. Among the patients, 142 (54.2%) had HPV-positive OSCC, and 120 (45.8%) had HPV-negative OSCC. Relationship distress was infrequently reported, and 69% of patients felt that their relationship had strengthened since the cancer diagnosis. Both HPV-positive patients (25%) and their partners (14%) reported feelings of guilt or responsibility for the diagnosis of an HPV-caused cancer. Concern over sexual, but not nonsexual, HPV transmission to partners was reported by 50%. Significant declines in the frequency of vaginal and oral sexual behaviors were reported at follow-up, regardless of tumor HPV status. From baseline to 6 months, significant increases in abstinence from vaginal sex (from 10% to 34%; P

To estimate changes in oral human papillomavirus (HPV) prevalence attributable to vaccination vs herd immunity, this national survey study uses National Health and Nutrition Examination Survey data to compare oral HPV prevalence for 4 types targeted by HPV vaccine and 33 nonvaccine types in unvaccinated US adults aged 18 to 59 years from 2009 to 2016.

Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5′-ATN-3′ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1, and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon (IFN) and nuclear factor kappa B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated ZNF750, PIK3CA, and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

Oral squamous cell carcinomas are a major cause of morbidity and mortality, and tobacco usage, alcohol consumption, and poor oral hygiene are established risk factors. To date, no large-scale case-control studies have considered the effects of these risk factors on the composition of the oral microbiome, nor microbial community associations with oral cancer. We compared the composition, diversity, and function of the oral microbiomes of 121 oral cancer patients to 242 age- and gender-matched controls using a metagenomic multivariate analysis pipeline. Significant shifts in composition and function of the oral microbiome were observed with poor oral hygiene, tobacco smoking, and oral cancer. Specifically, we observed dramatically altered community composition and function after tooth loss, with smaller alterations in current tobacco smokers, increased production of antioxidants in individuals with periodontitis, and significantly decreased glutamate metabolism metal transport in oral cancer patients. Although the alterations in the oral microbiome of oral cancer patients were significant, they were of substantially lower effect size relative to microbiome shifts after tooth loss. Alterations following tooth loss, itself a major risk factor for oral cancer, are likely a result of severe ecological disruption due to habitat loss but may also contribute to the development of the disease.

Background Oral human papillomavirus (HPV) infection is the principal underlying cause of a dramatic increase in oropharyngeal cancer. Dentistry can play an important role in developing clinical algorithms for secondary prevention. Methods The authors conducted this cross-sectional pilot study with practices of The National Dental Practice-Based Research Network. The authors evaluated the feasibility and acceptability of screening and testing procedures as judged by practitioners and patients. The authors used tablet devices for patient screening, obtaining consent, and administering a confidential oral HPV risk factor survey. Results Most patients (85%) were comfortable being asked about their cigarette use and their sexual behavior (69%) and were interested in participating again (79%). More than 90% of practitioners were comfortable with study procedures except the extra time required for patient participation (75% comfortable). There were no problems with oral rinse collection as reported by patients or practitioners. Conclusions It is feasible in community dental offices to collect oral rinses for HPV detection and to ask patients explicit questions about sexual history when using a tablet device for confidentiality. Practical Implications Discussing high-risk types of HPV and appropriately assessing that risk are a challenge for oral health care professionals. These results are positive from a research perspective but do not address the advisability of routine HPV screening in dentistry.

Oral human papillomavirus (HPV) infection is a cause of oropharyngeal squamous cell carcinoma, yet little is known about the epidemiology and natural history of infection.At a baseline and 3-month follow-up visit, 1000 young adults aged 18 to 30 years provided an oral rinse sample and completed a survey assessing demographic and behavioral risk factors. The oral rinse sample was analyzed for 37 types of HPV by use of a multiplex polymerase chain reaction assay. Factors associated with oral HPV detection were analyzed using univariate and bivariate logistic regression.The prevalence of oral HPV infection was 2.4% (95% CI: 1.4-3.4). Ever having consumed alcohol (OR, 0.2; 95% CI: 0.1-0.8), 5 or more lifetime open-mouth kissing (OR, 4.0; 95% CI: 1.1-14.8) or lifetime oral sex (OR, 4.0; 95% CI: 1.3-11.9) partners were associated with infection, controlling for lifetime vaginal sex partners. The incidence rate for oral HPV infection was 5.67 (95% CI: 3.12-8.16) per 1000 person-months. Incident infection was associated in univariate analysis with black race (OR, 4.7; 95% CI: 1.7-13.5) and having open-mouth kissed a new partner in the previous 3 months (OR, 2.6; 95% CI: 1.0-6.4).This study provides further evidence that oral sexual contact in the form of both oral-oral and oral-genital contact could play a role in the transmission of oral HPV.

The incidence of human papillomavirus (HPV)–positive oropharyngeal cancers is higher and increasing more rapidly among men than women in the United States for unknown reasons. We compared the epidemiology of oral oncogenic HPV infection between men and women ages 14 to 69 years (N = 9,480) within the U.S. National Health and Nutritional Examination Surveys (NHANES) 2009–2012. HPV presence was detected in oral DNA by PCR. Analyses were stratified by gender and used NHANES sample weights. Oral oncogenic HPV prevalence was higher among men than women (6.6% vs. 1.5%, P < 0.001), corresponding to 7.07 million men versus 1.54 million women with prevalent infection at any point in time during 2009–2012. Prevalence increased significantly with age, current smoking, and lifetime number of sexual partners for both genders (adjusted Ptrend < 0.02). However, men had more partners than women (mean = 18 vs. 7, P < 0.001). Although oncogenic HPV prevalence was similar for men and women with 0 to 1 lifetime partners, the male–female difference in prevalence significantly increased with number of lifetime partners (adjusted prevalence differences for none, 1, 2–5, 6–10, 11–20, and 20+ partners = 1.0%, 0.5%, 3.0%, 5.7%, 4.6%, and 9.3%, respectively). Importantly, the per-sexual partner increase in prevalence was significantly stronger among men than among women (adjusted synergy index = 3.3; 95% confidence interval, 1.1–9.7), and this increase plateaued at 25 lifetime partners among men versus10 partners among women. Our data suggest that the higher burden of oral oncogenic HPV infections and HPV-positive oropharyngeal cancers among men than women arises in part from higher number of lifetime sexual partners and stronger associations with sexual behaviors among men. Cancer Res; 75(12); 2468–77. ©2015 AACR.

We investigated the association of demographic and behavioral factors with oral human papillomavirus (HPV) load for 18 high-risk types among 211 individuals with prevalent high-risk HPV within the National Health and Nutrition Examination Survey 2009-2010. Factors independently associated with HPV load above the median included older age (odds ratio, 1.04 per year increase [95% confidence interval, 1.01-1.07]; P = .004) and intensity of current smoking (P for trend

Human papillomavirus-associated oral cancers comprise a distinct disease that is increasing in frequency in Western countries. Recent genomic landscape studies of oral cancers and of HPV-associated cervical cancers identified the most commonly mutated genes in each. Here we report a comprehensive analysis of 83 HPV-positive oropharyngeal cancers studied by whole genome sequencing (WGS), and an additional 46 tumors evaluated by the Cancer Genome Atlas project (TCGA) by exome sequencing. We confirmed recurrent mutations in previously reported, frequently mutated candidate driver genes including PIK3CA, as well as several novel gene targets, each occurring recurrently at frequencies of more than approximately 3%. Our WGS data demonstrated recurrent focal genomic instability associated with HPV insertional mutagenesis. We observed dramatic changes in genomic copy number variants (CNVs) at chromosome 3q as well as numerous other chromosomal regions that are recurrently gained or lost in HPV-positive tumors. RNA-Seq data from this collection of oral cancers defined differentially expressed transcript levels and other molecular alterations associated with single nucleotide variants (SNVs), CNVs and other genomic structural variants in the tumors. Together, our results reveal a unique pattern of somatic variants that distinguishes HPV+ oral cancers both from HPV- oral cancers as well as other HPV+ tumors arising in distinct tissues including the uterine cervix. These data shed new light on the molecular pathogenesis of oral cancers, and provide new opportunities for development of diagnostic and therapeutic strategies for affected patients. Citation Format: David E. Symer, Keiko Akagi, Kevin R. Coombes, Weihong Xiao, Robert K. L. Pickard, Amit Agrawal, Maura L. Gillison. Comprehensive genomic analysis of human papillomavirus-associated oral cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 132.

Tumor human papillomavirus (HPV) status is a prognostic factor for oropharyngeal cancer, but classification methods are not standardized. Here we validate the HPV classification methods used in US cooperative group trials. Tumor DNA and RNA purified from 240 paraffin-embedded oropharyngeal cancers diagnosed from 2000 to 2009 were scored as evaluable if positive for DNA and mRNA controls by quantitative polymerase chain reaction (PCR). Eighteen high-risk (HR) HPV types were detected in tumors by consensus PCR, followed by HR-HPV E6/7 oncogene expression analysis by quantitative reverse transcriptase PCR. The sensitivity (S), specificity (SP), and positive (PPV) and negative predictive values (NPV) of p16 expression detected by immunohistochemistry (IHC) and HPV16 detected by in situ hybridization (ISH) were evaluated in comparison with HR-HPV E6/7 oncogene expression. Interrater agreement among 3 pathologists was evaluated by κ statistics. Of 235 evaluable tumors, 158 (67%; 95% confidence interval, 61.2-73.3) were positive for HR-HPV E6/7 oncogene expression [HPV type 16 (92%), 18 (3%), 33 (3%), 35 (1%), or 58 (1%)]. p16 IHC had high sensitivity (S 96.8%, SP 83.8%, PPV 92.7%, and NPV 92.5%), whereas HPV16 ISH had high specificity (S 88.0%, SP 94.7%, PPV 97.2%, and NPV 78.9%) for HR-HPV oncogene expression. Interrater agreement was excellent for p16 (κ=0.95 to 0.98) and HPV16 ISH (κ=0.83 to 0.91). Receiver operating curve analysis determined the cross-product of p16 intensity score and percentage of tumor staining to optimally discriminate HR-HPV E6/7-positive and HR-HPV E6/7-negative tumors. p16 IHC and HPV16 ISH assays show excellent performance, with high sensitivity and specificity, respectively. A new validated H-score for p16 IHC assessment is proposed. Appropriate assay choice depends on clinical implications of a false-positive or false-negative test.

69 years was 6.9% (95% CI, 5.7%-8.3%) and of HPV type 16 was 1.0% (95% CI, 0.7%-1.3%). Oral HPV infection followed a bimodal pattern with respect to age, with peak prevalence among individuals aged 30 to 34 years (7.3%; 95% CI, 4.6%11.4%) and 60 to 64 years (11.4%; 95% CI, 8.5%-15.1%). Men had a significantly higher prevalence than women for any oral HPV infection (10.1% [95% CI, 8.3%12.3%] vs 3.6% [95% CI, 2.6%-5.0%], P.001; unadjusted prevalence ratio [PR], 2.80 [95% CI, 2.02-3.88]). Infection was less common among those without vs those with a history of any type of sexual contact (0.9% [95% CI, 0.4%-1.8%] vs 7.5% [95% CI, 6.1%-9.1%], P.001; PR, 8.69 [95% CI, 3.91-19.31]) and increased with number of sexual partners (P.001 for trend) and cigarettes smoked per day (P.001 for trend). Associations with age, sex, number of sexual partners, and current number of cigarettes smoked per day were independently associated with oral HPV infection in multivariable models.

Summary Background Human papillomavirus (HPV) is a cause of oropharyngeal cancer, but a role for HPV in the etiology of oral cavity squamous cell carcinomas (OCSCC) remains uncertain. Methods We sought to estimate the etiologic fraction for HPV among consecutive, incident OCSCC diagnosed from 2005 to 2011 at four North American hospitals. DNA and RNA purified from paraffin-embedded tumors were considered evaluable if positive for DNA and mRNA control genes by quantitative PCR. Fifteen high-risk (HR) HPV types were detected in tumors by consensus PCR followed by type-specific HR-HPV E6/7 oncogene expression by quantitative reverse-transcriptase PCR. P16 expression was evaluated by immunohistochemistry (IHC). A study of 400 cases allowed for precision to estimate an etiologic fraction of as low as 0% (97.5% confidence interval, 0–0.92%). Results Of 409 evaluable OCSCC, 24 (5.9%, 95%CI 3.6–8.2) were HR-HPV E6/7 expression positive; 3.7% (95%CI 1.8–5.5) for HPV16 and 2.2% (95%CI 0.8–3.6) for other HR-HPV types. HPV-positive tumors arose from throughout the oral cavity (floor of mouth [ n = 9], anterior tongue [6], alveolar process [4], hard palate [3], gingiva [1] and lip [1]) and were significantly associated with male gender, small tumor stage, poor tumor differentiation, and basaloid histopathology. P16 IHC had very good-to-excellent sensitivity (79.2%, 95%CI 57.9–92.9), specificity (93.0%, 95%CI 90.0–95.3), and negative-predictive value (98.6%, 95%CI 96.8–99.6), but poor positive-predictive value (41.3%, 95%CI 27.0–56.8) for HR-HPV E6/7 expression in OCSCC. Conclusion The etiologic fraction for HR-HPV in OCSCC was 5.9%. p16 IHC had poor positive predictive value for detection of HPV in these cancers.