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

Wizel, A.; Spence, M. D. A.; Mints, M.; Britton, W.; Okolo, O.; Yu, V.; Cioffi, I.; Caruana, S.; Troob, S. H.; Faquin, W. C.; Lin, D. T.; Tirosh, I.; Puram, S. V.; Parikh, A. S.; Drier, Y.

doi:10.1101/2025.04.21.649795

bioRxiv · 10.1101/2025.04.21.649795

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

Wizel, A.·Spence, M. D. A.·Mints, M.·Britton, W.·Okolo, O.·Yu, V.·Cioffi, I.·Caruana, S.·Troob, S. H.·Faquin, W. C.·Lin, D. T.·Tirosh, I.·Puram, S. V.·Parikh, A. S.·Drier, Y.

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Abstract

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a rare tumor that morphologically resembles high grade adenoid cystic carcinoma (ACC), yet exhibits indolent clinical behavior. Both demonstrate MYB proto-oncogene upregulation, but HMSC lacks the MYB translocation typically seen in ACC. Transcriptional changes in HMSC tumors remain uncharacterized. We performed single-cell RNA sequencing (scRNA-seq) on a human HMSC tumor and compared expression profiles with published ACC and oropharyngeal squamous cell carcinoma (OPSCC) scRNA-seq datasets. Primary malignant cells from HMSC (n=134) and ACC (n=980) clustered separately, and HMSC lacked bicellular differentiation into luminal and myoepithelial cells, distinguishing it from ACC. 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), suggesting an HPV-MYB association. This finding was validated in HPV-positive OPSCC, with 7/10 tumors showing MYB upregulation in HPVon versus HPVoff cells (p<0.05). A 264-gene signature from HPVon HMSC cells was also associated with worse prognosis in HPV+ OPSCC (p<0.003), suggesting an alternate role for HPV that has not been well characterized. Further validation of the HPV-MYB association and prognostically relevant HPV gene signature may improve patient stratification and therapeutic strategies in HPV-related malignancies.

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Wizel, A., Spence, M. D. A., Mints, M., Britton, W., Okolo, O., Yu, V., Cioffi, I., Caruana, S., Troob, S. H., Faquin, W. C., Lin, D. T., Tirosh, I., Puram, S. V., Parikh, A. S., Drier, Y.. 2025-04-28. Single-cell transcriptomic analysis of HPV-related multiphenotypic sinonasal carcinoma uncovers MYB-HPV association. https://doi.org/10.1101/2025.04.21.649795

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