Comprehensive Viral Genotyping Reveals Prognostic Viral Phylogenetic Groups in HPV16-Associated Squamous Cell Carcinoma of the Oropharynx

• Published in: Molecular cancer research 2022-10, Vol.20 (10), p.1489-1501
• Main Authors: Schrank, Travis P, Landess, Lee, Stepp, Wesley H, Rehmani, Hina, Weir, William H, Lenze, Nicholas, Lal, Asim, Wu, Di, Kothari, Aditi, Hackman, Trevor G, Sheth, Siddharth, Patel, Shetal, Jefferys, Stuart R, Issaeva, Natalia, Yarbrough, Wendell G
• Format: Article
• Language: English
• Subjects: Carcinoma, Squamous Cell - pathology; Genotype; Human papillomavirus 16 - genetics; Humans; Oropharyngeal Neoplasms - genetics; Papillomavirus Infections - pathology; Phylogeny; Prognosis; Tobacco Smoke Pollution
• ISSN: 1541-7786; 1557-3125; 1557-3125
• DOI: 10.1158/1541-7786.MCR-21-0443

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.