Three genera of human papillomavirus (HPV) infect the oral cavity and oropharynx— alpha (α), beta (β) and gamma (γ). While α-HPV infection is an established risk factor for head and neck cancers (HNC), the role of other genera remains unclear. We aimed to estimate the effect of α-, β-, γ-HPV on HNC using a hospital-based case-control study.
We recruited incident HNC cases (396) and controls (439), frequency-matched by age and sex from four main referral hospitals in Montreal, Canada. We collected information on sociodemographic and behavior characteristics using in-person interviews, and tested rinse, brush and tumor specimens for HPV genotypes. We estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the effect of HPV on HNC using logistic regression, adjusting for confounding. We conducted probabilistic bias analysis to account for potential exposure misclassification, selection bias, and residual confounding.
α-HPV genus had a strong effect on HNC, particularly HPV16 (aOR=22.6; 95% CI: 10.8, 47.2). β-HPV was more common among controls (aOR=0.80; 95% 0.57, 1.11). After adjustment for HPV16, we found weaker evidence for γ-HPV (aOR= 1.29; 95% CI: 0.80, 2.08). Combined bias analyses for HPV16 increased the strength of the point estimate, but added imprecision (aOR=54.2, 95% CI: 10.7, 385.9).
α-HPV, especially HPV16, appears to increase the risk for HNC, while there is little evidence for an effect of β- or γ-HPV. β-HPV may have a preventive effect, while γ-HPV may increase the risk of HNC, although to a lesser extent than that of α-HPV. Results for cutaneous HPV were imprecise and less conclusive. Due to possible epidemiologic biases, the true relation between HPV and HNC could be underestimated in the literature. Further improvement in current methods and more studies of the biologic mechanisms of the three genera in HNC development are warranted.
- • Infection with α-HPV, especially HPV16, has a strong effect on HNC.
- • β-HPV infection could have a protective effect against HNC
- • There is a weak evidence that γ-HPV infection increases the risk of HNC
- • Presence of systemic biases attenuates the estimated HPV16-HNC relation
Over 90% of head and neck cancers (HNC) are squamous cell carcinomas that affect the oral cavity, lips, pharynx, or larynx . HNC is often diagnosed at late stages, has high morbidity and mortality , and one of the highest suicide rates of all cancers . Following many years of decline, the incidence of HNC has increased in recent decades in North America with an estimated annual percentage increase of 1.2% in Canada , and 0.8% in the United States . The rising incidence is mainly affecting the oropharynx and is driven by human papillomavirus (HPV) infection . Indeed, HPV-related HNC are now the most common cancers associated with these viruses in Canada .
Over 200 genotypes of HPVs have been discovered to date which are divided into five genera. Information on classification and biology of these viruses can be found elsewhere , and an up to date database of these viruses can be found in the International Human Papillomavirus Reference Center . Three of these HPV genera affect the oral cavity: alpha (α), beta (β), and gamma (γ) . It is worth noting that β- and γ-HPV genera have been often described as cutaneous HPV because they were first isolated from the skin, whereas α-HPV are known as mucosal for being isolated in cervical samples . Oral HPV infection by the α-genus, specifically HPV 16, has been responsible for the increase in HNC incidence . However, the frequent detection of β and γ HPV genera in oral samples and their presence in head and neck papillomas raises questions about the potential etiological role in HNC. Yet, evidence on the effects of β and γ HPV on HNC is limited. In particular, the characteristics of the study population (e.g., age, sex, ethnicity, behavior) and the methods used for oral sample collection, processing, and HPV detection may affect the prevalence and effects of HPVs.
Agalliu et al., used a nested case-control design and found associations between oral infection by α-, β-, and γ-HPV and the development of HNC . However, this study sampled only 132 HNC cases and 396 controls (nested within 2 prospective cohorts) and used only mouthwash samples to detect oral HPV infection. Additional studies using a larger sample size, conducted in different populations and using multiple methods of sampling HPV are required to better characterize the role of β and γ HPVs in HNC.
Therefore, we aimed to estimate the effect of α-, β-, and γ- HPVs on HNC risk using oral samples from a large hospital-based case-control study. We also investigated the presence of HPV infection according to α-, β-, and γ- HPVs in a subsample of participant cases (n = 121) for whom tumors were available, and evaluated concordance with oral HPV. Lastly, we conducted sensitivity analyses to test the robustness of our findings for possible sources of bias including HPV misclassification, selection bias, and residual confounding.