Researchers may have identified key genetic differences between human papillomavirus–associated and independent sinonasal squamous cell carcinoma, offering new insights into tumor development, prognosis, and potential treatment strategies.
Sinonasal squamous cell carcinoma (SNSCC) arises in the nasal cavity and paranasal sinuses, with an incidence of approximately 0.4 cases per 100,000 individuals annually. About one-quarter of these tumors are linked to high-risk human papillomavirus (HPV), while most remain HPV-independent.
In the study, the researchers analyzed tumor samples from 56 patients. Among these, 37 were HPV-associated based on the presence of high-risk HPV E6/E7 mRNA and 19 were HPV-independent. Patients with HPV-associated cancer were typically younger, with a mean age of 60.8 years compared with 66.3 years among those with HPV-independent cancer.
Genetic analysis revealed distinct tumorigenic pathways for the two groups. HPV-independent tumors showed high frequencies of TP53 mutations, found in approximately 70% of cases, along with alterations in NOTCH1, KRAS, CDKN2A, COL2A1, and FAT4, consistent with patterns seen in other head and neck cancers not linked to HPV.
In contrast, HPV-associated tumors demonstrated frequent mutations in KMT2D, FGFR3, and KMT2C, as well as additional recurrent mutations in UBXN11, AP3S1, MT-ND4, and MT-ND5. Many of these mutations weren't observed in HPV-associated head and neck or cervical cancers, suggesting that HPV-associated SNSCC may represent a distinct biological subtype.
Certain mutations were linked to overall survival. TP53 mutations in HPV-independent SNSCC were associated with significantly lower survival. In HPV-associated cases, KMT2D and FGFR3 mutations were also linked to decreased survival.
The researchers also analyzed mutational signatures. HPV-associated tumors exhibited a strong APOBEC signature, common in HPV-driven cancers, while smoking-related signatures weren't enriched in either group, despite many patients having a history of tobacco use.
Viral integration analysis showed that HPV frequently integrated into host DNA near genes involved in epithelial stem cell maintenance, including TP63 and KLF5. Many of these integrations occurred at genomic fragile sites and repetitive elements, resembling patterns seen in cervical and other head and neck cancers linked to HPV.
Pathway analysis suggested different molecular drivers for each subtype. In HPV-associated tumors, PI3K and YAP/TAZ pathways were highly activated, suggesting that combined inhibition of these pathways may offer a therapeutic approach. In HPV-independent tumors, MYC and RAS/PI3K pathways were more prominent, indicating a separate set of drug targets.
To explore the findings experimentally, the researchers developed an HPV-associated SNSCC cell line from one patient’s tumor. Laboratory testing showed that combining PI3K inhibition with YAP/TAZ pathway blockade produced a strong synergistic effect in reducing tumor cell growth.
The results of the study clarified the molecular landscape of SNSCC and highlighted potential precision treatments based on HPV status and specific genetic alterations. The researchers emphasized the need for larger, multi-institutional studies to validate the results because of the rarity of the disease.
Full disclosures can be found in the study.
Source: Nature Communications