Introduction:
Human papillomavirus (HPV) has been shown to contribute to a growing proportion of not only oropharyngeal squamous cell carcinoma (OPSCC), but also sinonasal squamous cell carcinoma (SNSCC), which constitutes a rare but highly morbid cancer. Previous work has shown that different HPV lineages, sub-lineages, and individual genetic variants are associated with notable differences in carcinogenicity and clinical outcomes in HPV-driven cervical cancer as well as HPV+ OPSCC. However, for HPV+ SNSCC, the genomic landscape and molecular impact of HPV remains to be explored. Here, we undertake the first analysis of paired HPV and somatic whole-genome sequences from a cohort of patients with SNSCC. We aim to define viral genotype, lineage, and sub-lineage distribution as well as mutational processes at play in viral and somatic genomes.

Methods: We performed a universal HPV-type screening on 43 formalin-fixed paraffin-embedded tissue samples from SNSCC cases. We performed whole-genome sequencing of viral, somatic, and paired normal blood DNA for cases containing high-risk HPV types (36 cases). In cases with multiple high-risk HPV types present, all types underwent sequencing using a universal sequencing protocol. We aligned each HPV sample to a reference strain of the corresponding genotype.

Results: Among 43 cases of SNSCC which were screened for HPV, 4 cases were negative for HPV, and 3 cases contained only low-risk HPV (HPV11). The 36 remaining cases were found to contain at least one high-risk HPV type: 26 cases contained a single high-risk genotype, 9 cases contained 2 high-risk genotypes, and 1 case contained 3 high-risk genotypes. Among cases exhibiting high-risk genotypes, 5 cases also contained a low-risk genotype (HPV11 or 84). HPV16 and HPV18 were the most prevalent high-risk genotypes detected, accounting for 39.1% (N=18) and 26.1% (N=12) of genotypes, respectively. HPV33, HPV35, and HPV59 were each present at a rate of 6.5% (N=3 for each). HPV45 and HPV56 were each detected at a rate of 4.3% (N=2 for each), and HPV39 was detected at a rate of 2.1% (N=1).  For cases containing more than one high-risk genotype, either HPV16 or HPV18 was present in all but one case, which contained HPV33 and HPV59. We are continuing to explore HPV lineage and sub-lineage distribution, as well as presence of mutations in the viral and somatic genomes.

Conclusion: Using samples from 36 cases of HPV+ SNSCC, we demonstrate here that distribution of HPV genotypes in HPV+ SNSCC is varied, exhibiting a plurality of HPV16, but also large numbers of HPV18, and in smaller amounts several other high-risk HPV types. Interestingly, while etiologic hypotheses have proposed an anatomic link between HPV+ OPSCC and HPV+ SNSCC, the pattern seen here differs from the distribution typically observed in HPV+ OPSCC. This study will contribute to a better understanding of the genomic landscape of HPV+ SNSCC, which may ultimately influence personalized treatment decision making for patients with HPV+ SNSCC.