Human and Viral Whole-Genome Sequencing Reveals HPV-Driven Carcinogenesis and Mutational Signatures in Sinonasal Squamous Cell Carcinoma

Abstract Sinonasal squamous cell carcinoma (SNSCC) is an aggressive malignancy that has not seen therapeutic advance in decades. Historically attributed to inhaled carcinogens, SNSCC is also incidentally associated with human papillomavirus (HPV), the major oncogenic driver in over 80% of adjacent oropharyngeal cancers. While HPV status guides staging and treatment in oropharyngeal cancer, the oncogenic consequences of host–virus interactions in SNSCC remain incompletely defined. Here, through paired host and viral whole-genome sequencing of 21 cases, we map the genomic footprint of HPV in SNSCC. Strikingly, less-studied genotypes such as HPV45 and 51 constitute driver infections. APOBEC activity was detected in a subset of HPV-associated SNSCC, while Signature 12 emerged as the most frequent dominant mutational signature and showed transcriptional strand bias consistent with an in vivo mutational process. Viral integration events, including extrachromosomal DNA (ecDNA)-associated HPV–human ecDNA amplicons, further contribute to tumor evolution. Statement of Significance Paired host and viral whole-genome sequencing identifies non-HPV16 high-risk HPV genotypes (e.g., HPV45 and 51) and HPV–human ecDNA amplicons as primary oncogenic drivers of sinonasal squamous cell carcinoma (SNSCC). A distinct mutational landscape, characterized by frequent Signature 12 activity and APOBEC mutagenesis in a subset of tumors, distinguishes SNSCC from other HPV-associated cancers. Importantly, non-HPV16 high-risk HPV genotypes play an underrecognized role in SNSCC, and support their inclusion in routine clinical testing.