Do cutaneous human papillomavirus genotypes affect head and neck cancer? Evidence and bias-correction from a case-control study

1Introduction

Over 90% of head and neck cancers (HNC) are squamous cell carcinomas that affect the oral cavity, lips, pharynx, or larynx [1] . HNC is often diagnosed at late stages, has high morbidity and mortality [2] , and one of the highest suicide rates of all cancers [34] . 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 [56] , and 0.8% in the United States [7] . The rising incidence is mainly affecting the oropharynx and is driven by human papillomavirus (HPV) infection [8] . Indeed, HPV-related HNC are now the most common cancers associated with these viruses in Canada [9] .

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 [1011] , and an up to date database of these viruses can be found in the International Human Papillomavirus Reference Center [12] . Three of these HPV genera affect the oral cavity: alpha (α), beta (β), and gamma (γ) [13] . 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 [11] . Oral HPV infection by the α-genus, specifically HPV 16, has been responsible for the increase in HNC incidence [814] . However, the frequent detection of β and γ HPV genera in oral samples and their presence in head and neck papillomas [13] 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 [15] 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 [16] . 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.