Findings from a comprehensive genome-wide study of sinonasal squamous cell carcinomas demonstrated that human papillomavirus (HPV) can drive tumorigenesis in some cases, and these tumors exhibit similar mutational patterns to those seen in HPV-associated cervical and head and neck squamous cell carcinoma. The results of the molecular analysis were published in Nature Communications.
“Our findings provide important genomic insights and advance the understanding of these rare sinonasal tumors,” stated co-first study author Fernando Zamuner, PhD, Faculty Research Associate in the Department of Otolaryngology-Head and Neck Surgery at Johns Hopkins University School of Medicine.
Study Methods and Results
Previous study findings have shown that about 25% of sinonasal squamous cell carcinomas are associated with HPV. But until now, researchers were unsure if HPV drove the tumorigenesis in sinonasal squamous cell carcinomas or if it was a neutral bystander.
The study authors conducted a comprehensive molecular analysis of HPV-associated sinonasal squamous cell carcinomas as well as HPV-independent sinonasal squamous cell carcinomas. They performed high-throughput DNA sequencing on tissue samples from 56 patients with sinonasal squamous cell carcinomas as well as comparator DNA samples. Thirty-seven of the participants had HPV-associated disease, and these patients were associated with a younger age at diagnosis.
Patients with HPV-associated sinonasal squamous cell carcinoma had frequent mutations in the KMT2D, FGFR3, KMT2C, GOLGA5, TET1, and ARID1B cancer driver genes. A second sample group with HPV-associated disease demonstrated similar mutation frequencies in KMT2D, FGFR3, KMT2C, and ARID1B. Mutations in KMT2D and FGFR3 genes were associated with reduced overall survival.
Recurrent mutations not seen in other tumor types found in HPV-associated sinonasal squamous cell carcinomas included KMT2C N729D, AP3S1 P158L, UBXN11, MT-ND4, and MT-ND5. Additionally, hotspot mutations were found at the E542K/E545K location in PIK3CA and S249C area in FGFR3.
“The surprising thing is that we identified five new recurrent mutations that are specific for HPV-associated sinonasal squamous cell carcinoma that are not found in other tumors. We are now trying to figure out the biology behind those and their functional importance,” said senior study author Nyall London Jr, MD, PhD, Associate Professor of Otolaryngology-Head and Neck Surgery at the Johns Hopkins University School of Medicine.
Comparatively, HPV-independent sinonasal squamous cell carcinomas frequently showed mutations in TP53, NOTCH1, KRAS, CDKN2A, COL2A1, FAT4, FBXW7, and ROS1 genes. A second sample group with HPV-independent disease confirmed similar mutation frequencies in TP53, NOTCH1, CDKN2A, COL2A1, and FAT4. Mutations in TP53 were associated with worse overall survival.
When comparing HPV-associated sinonasal squamous cell carcinomas with other HPV-associated head and neck cancers and cervical cancers, sinonasal cancers similarly showed enrichment of APOBEC mutagenesis, viral integration at known hotspots, and frequent epigenetic regulator alterations.
Significant activity was seen for HPV-associated sinonasal cancers in the PI3K pathway and the YAP/TAZ pathways, compared with in the PI3K, RAS, and MYC pathways in HPV-independent disease.
Then the researchers established an HPV-associated sinonasal squamous cell carcinoma cell line to determine possible treatment approaches for these patients. Combinational small molecule inhibition of the YAP/TAZ and PI3K pathways with verteporfin and alpelisib was found to synergistically suppress clonogenicity in HPV-associated sinonasal squamous cell carcinomas. For HPV-independent sinonasal cancers, targeting the MYC pathway plus inhibition of the RAS/PI3K pathway was more effective.
Disclosure: For full disclosures of the study authors, visit nature.com.
