Sinonasal squamous cell carcinoma (SNSCC) is an aggressive head and neck cancer of the sinonasal cavity which has not benefitted from therapeutic advances over decades1. Though historically attributed to inhaled carcinogens such as hardwood dust and tobacco smoking2, SNSCC is incidentally associated with human papillomavirus (HPV)3,4. Importantly, HPV is the primary oncogenic driver of >80% of anatomically adjacent oropharyngeal cancers5. While viral status drives clinical staging and treatment guidelines in these malignancies6,7, 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.

The authors have declared no competing interest.

D. L. Faden reports grants from the NIH/NIDCRK23DE029811, NIH/NIDCRR03DE030550, and NIH/NCIR21CA267152 during the conduct of the study as well as grants from Bristol Myers Squibb, Calico, and Haystack(Quest); other support from Predicine, BostonGene, and Neogenomics; and personal fees from Merck, Chrysalis Biomedical Advisors, and Arcadia outside the submitted work; in addition, D. L. Faden has a patent for 169511-00058-MEEI2024-32 pending. No disclosures were reported by the other authors.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRBs of Mass General Brigham and Vanderbilt University Medical Center gave ethical approval for this work. All patients provided written informed consent under protocols approved by both institutions.

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Yes

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Authors’ Disclosures: D. L. Faden reports grants from the NIH/NIDCRK23DE029811, NIH/NIDCRR03DE030550, and NIH/NCIR21CA267152 during the conduct of the study as well as grants from Bristol Myers Squibb, Calico, and Haystack(Quest); other support from Predicine, BostonGene, and Neogenomics; and personal fees from Merck, Chrysalis Biomedical Advisors, and Arcadia outside the submitted work; in addition, D. L. Faden has a patent for 169511-00058-MEEI2024-32 pending. No disclosures were reported by the other authors.

All data produced in the present work are contained in the manuscript.