TP53mutations and CDKN2Amutations/deletions are highly recurrent molecular alterations in the malignant progression of sinonasal papillomas

Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with a synchronous or metachronous sinonasal carcinoma in a subset of cases. Our group recently identified mutually exclusive EGFRmutations and human papillomavirus (HPV) infection in inverted sinonasal papillomas and frequent KRASmutations in oncocytic sinonasal papillomas. We also demonstrated concordant mutational and HPV infection status in sinonasal papilloma-associated sinonasal carcinomas, confirming a clonal relationship between these tumors. Despite our emerging understanding of the oncogenic mechanisms driving formation of sinonasal papillomas, little is currently known about the molecular mechanisms of malignant progression to sinonasal carcinoma. In the present study, we utilized targeted next-generation DNA sequencing to characterize the molecular landscape of a large cohort of sinonasal papilloma-associated sinonasal carcinomas. As expected, EGFRor KRASmutations were present in the vast majority of tumors. In addition, highly recurrent TP53mutations, CDKN2Amutations, and/or CDKN2Acopy-number losses were detected; overall, nearly all tumors (n= 28/29; 96.6%) harbored at least one TP53or CDKN2Aalteration. TERTcopy-number gains also occurred frequently (27.6%); however, no TERTpromoter mutations were identified. Other recurrent molecular alterations included NFE2L2and PIK3CAmutations and SOX2, CCND1, MYC, FGFR1, and EGFRcopy-number gains. Importantly, TP53mutations and CDKN2Aalterations were not detected in matched sinonasal papillomas, suggesting that these molecular events are associated with malignant transformation. Compared to aerodigestive tract squamous cell carcinomas from The Cancer Genome Atlas (TCGA) project, sinonasal papilloma-associated sinonasal carcinomas have a distinct molecular phenotype, including more frequent EGFR, KRAS, and CDKN2Amutations, TERTcopy-number gains, and low-risk human papillomavirus (HPV) infection. These findings shed light on the molecular mechanisms of malignant progression of sinonasal papillomas and may have important diagnostic and therapeutic implications for patients with advanced sinonasal cancer.