Single-cell transcriptomic analysis of HPV-related multiphenotypic sinonasal carcinoma uncovers MYB-HPV association

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a rare tumor that morphologically resembles high-grade adenoid cystic carcinoma (ACC) but exhibits indolent clinical behavior. Both demonstrate MYB proto-oncogene upregulation, though HMSC lacks the MYB translocation characteristic of ACC. We performed single-cell RNA sequencing on an HMSC tumor and compared expression patterns with published ACC and oropharyngeal squamous cell carcinoma (OPSCC) datasets. Malignant HMSC cells clustered separately from ACC and lacked bicellular luminal and myoepithelial differentiation. A greater proportion of HMSC cells expressing HPV-related genes (HPVon) expressed MYB (83% vs. 62%, p = 0.022) and MYB targets (p = 6.4 × 10⁻⁶), supporting an HPV-MYB association. Validation in HPV + OPSCC revealed MYB upregulation in HPVon cells from 7/10 tumors (p < 0.05). A 264-gene signature from HPVon HMSC cells correlated with worse prognosis in HPV + OPSCC (p < 0.003), suggesting an alternate role for HPV. Further validation of the HPV-MYB association and gene signature may improve therapeutic strategies in HPV-related malignancies.