Methylation Drivers and Prognostic Implications in Sinonasal Poorly Differentiated Carcinomas

SIMPLE SUMMARY: Poorly differentiated sinonasal carcinomas (PDSNCs) are rare neoplasms that include a wide spectrum of malignancies characterized by alteration in different epigenetic mechanisms (SWI/SNF complex, IDH2, NUT). The aim of our study was to verify if the identification of specific genetic and epigenetic alterations can be useful to recognize different clinico-pathological subsets of PDSNCs to guide treatment decisions. In our cohort, 14 cases showed alterations in SWI/SNF complex or IDH2 genes, which were associated with a higher global DNA methylation level and worst prognosis. The integration of genetic and epigenetic features appears to be a good strategy to improve the clinico-pathological classification of these tumors and to recognize distinct prognostic entities that deserve tailored clinical management. ABSTRACT: Background: Poorly differentiated sinonasal carcinomas (PDSNCs) are rare and aggressive malignancies, which include squamous cell carcinoma (SCC), sinonasal undifferentiated carcinoma (SNUC), and neuroendocrine carcinomas (NEC). Several epigenetic markers have been suggested to support the histopathological classification, predict prognosis, and guide therapeutic decision. Indeed, molecularly distinct subtypes of sinonasal carcinomas, including SMARCB1-INI1 or SMARCA4 deficient sinonasal carcinoma, isocitrate dehydrogenase (IDH)-mutant SNUC, ARID1A mutant PDSNCs, and NUT carcinomas, have recently been proposed as separate entities. Identification of aberrant DNA methylation levels associated with these specific epigenetic driver genes could be useful for prognostic and therapeutic purpose. Methods: Histopathological review and immunohistochemical study was performed on 53 PDSNCs. Molecular analysis included mutational profile by NGS, Sanger sequencing, and MLPA analyses, and global DNA methylation profile using LINE-1 bisulfite-PCR and pyrosequencing analysis. Results: Nine SWI/SNF complex defective cases and five IDH2 p.Arg172x cases were identified. A significant correlation between INI-1 or IDH2 defects and LINE-1 hypermethylation was observed (p = 0.002 and p = 0.032, respectively), which were associated with a worse prognosis (p = 0.007). Conclusions: Genetic and epigenetic characterization of PDSNCs should be performed to identify distinct prognostic entities, which deserved a tailored clinical treatment.