ABSTRACT: Importance:Prospective studies are needed to examine the temporal relationship between oral human papillomavirus (HPV) detection and risk of head and neck squamous cell carcinoma (HNSCC). Moreover, the oral cavity contains a wide spectrum of ?-, ?-, and ?-HPV types, but their association with risk of HNSCC is unknown. Objective:To prospectively examine associations between ?-, ?-, and ?-HPV detection in the oral cavity and incident HNSCC. Design:A nested case-control study was carried out among 96?650 participants, cancer free at baseline, with available mouthwash samples in 2 prospective cohort studies: (1) the American Cancer Society Cancer Prevention Study II Nutrition Cohort and (2) the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident cases of HNSCC (n?=?132) were identified during an average 3.9 years of follow-up in both cohorts. Three controls per case (n?=?396) were selected through incidence density sampling and matched on age, sex, race/ethnicity, and time since mouthwash collection. Methods:Through a next-generation sequencing assay, DNA from ?-, ?-, and ?-HPV types were detected. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% CIs, adjusting for smoking history, alcohol consumption, and detection of HPV-16 for ?- and ?-HPVs. Main Outcomes and Measures:Incident HNSCC, which includes cancers of the oropharynx, oral cavity, and larynx. Results:A total of 132 participants developed HNSCC during the follow-up period (103 men and 29 women; average age at baseline, 66.5 years). Oral HPV-16 detection was associated with incident HNSCC (OR, 7.1; 95% CI, 2.2-22.6), with positive association for oropharyngeal SCC (OR, 22.4; 95% CI, 1.8-276.7), but not for oral cavity (OR, 4.5; 95% CI, 0.6-34.7) or laryngeal SCCs (OR, 0.11; 95% CI, 0.01-834.80). Detection of ?1-HPV-5 and ?2-HPV-38 types, as well as ?-11 and ?-12 species, had ORs for HNSCC that ranged from 2.64 to 5.45 (P?
