Human papillomavirus–positive (HPV+) squamous cell carcinoma of the oropharynx (OPSCC) is the most prevalent HPV-associated malignancy in the United States and is primarily caused by HPV subtype 16 (HPV16). Favorable treatment outcomes have led to increasing interest in treatment deescalation to reduce treatment-related morbidity. Prognostic biomarkers are needed to identify appropriately low-risk patients for reduced treatment intensity. Targeted DNA sequencing including all HPV16 open reading frames was performed on tumors from 104 patients with HPV16+ OPSCC treated at a single center. Genotypes closely related to the HPV16-A1 reference were associated with increased numbers of somatic copy-number variants in the human genome and poor recurrence-free survival (RFS). Genotypes divergent from HPV16-A1 were associated with favorable RFS. These findings were independent of tobacco smoke exposure. Total RNA sequencing was performed on a second independent cohort of 89 HPV16+ OPSCC cases. HPV16 genotypes divergent from HPV16-A1 were again validated in this independent cohort, to be prognostic of improved RFS in patients with moderate (less than 30 pack-years) or low (no more than 10 pack-years) of tobacco smoke exposure. In summary, we show in two independent cohorts that viral sequence divergence from the HPV16-A1 reference is correlated with improved RFS in patients with moderate or low tobacco smoke exposure.


HPV16 genotype is a potential biomarker that could be easily adopted to guide therapeutic decision-making related to deescalation therapy.

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