Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of ''looping'' by which HPV integrant-mediated DNA replication and recombination may result in viral-host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.
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.
MethodsWe 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. 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%; P adj = .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%; P adj = .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.
Results
Between
ConclusionHPV 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.
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 rising more rapidly among men than women in the United States (U.S.) for unknown reasons. We compared the epidemiology of oral oncogenic HPV infection between men and women aged 14-69 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 utilized 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 vs. 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 p-trends<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 0-1 lifetime partners, the male-female difference in prevalence significantly increased with number of lifetime partners (adjusted prevalence differences for none, one, 2-to-5, 6-to-10, 11-to-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 women (adjusted Synergy Index=3.3; 95%CI=1.1-9.7), and this increase plateaued at 25 lifetime partners among men vs.10 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.
Prophylactic human papillomavirus (HPV) vaccination has been recommended for routine use in US females since 2006 and males since 2011 for the prevention of anogenital HPV infections. 1 Although studies have demonstrated high vaccine efficacy in reducing prevalence of oral HPV infection, 2 prevention of oral HPV infections and oropharyngeal cancers is not a vaccine indication because of lack of randomized trials. Also lacking are surveillance studies for herd protection against oral HPV infections. 3 We investigated evidence for herd protection against oral HPV infections in unvaccinated US men and women aged 18 to 59 years via temporal (2009-2016) comparisons of oral HPV prevalence for 4 vaccine types (HPV-16/-18/-6/-11) and 33 nonvaccine types.
Background
Oral HPV infection elevates risk of oropharyngeal cancer, but its natural history is unknown. Natural history studies necessitate validation of an automated, high-throughput method for HPV genomic DNA detection in oral rinse samples (ORS).
Objectives
To compare agreement of oral HPV detection in ORS processed by a magnetic-bead based automated platform to a previous gold-standard, manual protein-precipitation method. Agreement was compared to that of repeat sampling and repeat HPV testing.
Study Design
HIV-infected individuals (n=100) provided two ORS collected 15 minutes apart. DNA was isolated from equal aliquots by either a protein-precipitation based (Puregene, Qiagen) or magnetic-bead based (QIAsymphonyTM SP, Qiagen) method. HPV DNA was detected and type-specified by consensus primer PCR and reverse line blot hybridization. The kappa statistic was used to assess overall agreement (OA) and agreement on a positive test (Ps+).
Results
The DNA purification methods had very high agreement for categorizing an individual as HPV infected (OA = 0.95; Ps+ = 0.94) as well as for detection of HPV type-specific infection (OA = 0.99; Ps+ = 0.88) in ORS. Agreement for detection of HPV type-specific infection was greater than that observed with repeat oral rinse sampling (OA = 0.99, Ps+ = 0.76) but comparable to inter-assay agreement (OA = 1.00, Ps+ = 0.90).
Conclusions
HPV detection in ORS processed with a magnetic-bead based automated platform will facilitate large natural history studies of oral HPV infection necessary to evaluate the potential use of oral HPV detection in oral cancer screening.
Human papillomavirus (HPV) 58 is a high-risk HPV type associated with progression to invasive genital carcinomas. We developed six monoclonal antibodies (mAbs) against HPV58 L1 virus-like particles that bind conformational epitopes on HPV58. The hybridoma cell lines were adapted to serum- and animal component-free conditions and the mAb supernatants were affinity-purified. The six mAbs neutralized HPV58 pseudoviruses (PsVs) and ‘quasivirions’ with different capacities. The mAbs differed in their ability to prevent PsV58 attachment to HaCaT cells, to the extracellular matrix (ECM) deposited by HaCaT cells, to heparin and to purified human laminin 5, a protein in the ECM. These mAbs provide a unique set of tools to study the binding properties of a previously untested, high-risk HPV type and the opportunity to compare these characteristics with the binding of other HPV types.
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