Mirabello, Lisa J

Abstract Sinonasal squamous cell carcinoma (SNSCC) is an aggressive head and neck cancer of the sinonasal cavity which has not benefitted from therapeutic advances over decades 1 . Though historically attributed to inhaled carcinogens such as hardwood dust and tobacco smoking 2 , SNSCC is incidentally associated with human papillomavirus (HPV) 3,4 . Importantly, HPV is the primary oncogenic driver of >80% of anatomically adjacent oropharyngeal cancers 5 . While viral status drives clinical staging and treatment guidelines in these malignancies 6,7 , the potentially oncogenic consequences and prognostic value of host–virus interactions in SNSCC remain incompletely defined. Here, through paired host and viral whole-genome sequencing (WGS), we map the genomic footprint of HPV in SNSCC. Strikingly, lesser studied strains such as HPV45, 51, and 39 constitute driver infections in this rare but clinically credentialed cancer, where extrachromosomal DNA (ecDNA)-associated viral integration and APOBEC mutagenesis are shown to underpin somatic tumor evolution. Statement of Significance Paired host viral and whole-genome sequencing of SNSCC nominates HPV as a primary oncogenic driver of SNSCC. HPV–human ecDNA amplicons harboring noncanonical strains such as HPV45, 51 mediate viral carcinogenesis. Routine clinical diagnostic HPV panels should be expanded to capture the activity of lesser studied strains.