Molecular patterns and mechanisms of tumorigenesis in HPV-associated and HPV-independent sinonasal squamous cell carcinoma
- Fernando T. Zamuner
- Sreenivasulu Gunti
- Gabriel J. Starrett
- Farhoud Faraji
- Tiffany Toni
- Anirudh Saraswathula
- Kenny Vu
- Anuj Gupta
- Yan Zhang
- Daniel L. Faden
- Michael E. Bryan
- Theresa Guo
- Nicholas R. Rowan
- Murugappan Ramanathan
- Andrew P. Lane
- Carole Fakhry
- Gary L. Gallia
- Clint T. Allen
- Lisa M. Rooper
- Nyall R. London
2025-06-11
Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly understood due to its rarity. A subset of SNSCC is associated with human papillomavirus (HPV), but it is unclear whether HPV drives tumorigenesis or acts as a neutral bystander. Here, we show that HPV-associated SNSCC shares mutational patterns found in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations, hotspot mutations in PI3K and FGFR3 , enrichment of APOBEC mutagenesis, viral integration at known hotspots, and frequent epigenetic regulator alterations. We identify HPV-associated SNSCC-specific recurrent mutations in KMT2C , UBXN11 , AP3S1 , MT-ND4 , and MT-ND5 , with KMT2D and FGFR3 mutations correlating with reduced overall survival. We establish an HPV-associated SNSCC cell line, showing that combinatorial small-molecule inhibition of YAP/TAZ and PI3K synergistically suppresses clonogenicity. Combining YAP/TAZ blockade with vertical PI3K inhibition may benefit HPV-associated SNSCC, whereas targeting MYC and horizontal inhibition of RAS/PI3K may suit HPV-independent SNSCC.