Background  Understanding the genetic basis for the molecular classification of sinonasal undifferentiated carcinoma (SNUC) based on SMARCB1 may improve our understating regarding the nature of the disease. The objective of the study was to compare the genetic profile of SMARCB1-retained (SR-SNUC) and SMARCB1-deficient SNUC (SD-SNUC). Methods  Formalin-fixed, paraffin-embedded tissue from treatment-naive patients with SNUC were selected. Three cases of SR-SNUC, four cases of SD-SNUC, and four samples of nontumor tissue (control samples) were selected. Ribonucleic acid (RNA) sequencing was performed. Results  SR-SNUC had a higher number of variants (1 variant for every 15,000 bases) compared with SD-SNUC (1 variant every 29,000 bases). The ratio of missense to silent mutation ratio was higher for SR-SNUC (0.8) as compared with SD-SNUC (0.7). Approximately 1,500 genes were differentially expressed between SR-SNUC and SD-SNUC. The genes that had a higher expression in SR-SNUC included TPD52L1, B3GNT3, GFY, TJP3, ELL3, CYP4F3, ALDH3B2, CKMT1B, VIPR1, SLC7A5, PPP2R2C, UPK3B, MUC1, ELF5, STY7, and H2AC14. The gene that had a higher expression in SD-SNUC was ZFHX4. Most of these genes were related to either protein translation or immune regulation. The most common ( n  = 3, 75%) mechanisms of loss of SMARCB1 gene in SD-SNUC was loss of heterozygosity. Conclusion  RNA sequencing is a viable and informative approach for genomic profiling of archival SNUC samples. Both SR-SNUC and SD-SNUC were noted to have distinct genetic profiles underlying the molecular classification of these diseases.

Sinonasal undifferentiated carcinoma (SNUC) is a highly malignant tumor in the nasal cavity or paranasal sinuses. Morphoproteomics has defined its biology to some degree, allowing the identification of targeted therapeutic options with clinical efficacy [1]. This study\'s objective was to identify putative SNUC pathways that are known to pose a block in differentiation both in early embryogenesis and in tumorigenesis or that might promote metastasis and recurrent disease.
METHODS: Morphoproteomic analysis of SNUC from a case study of this patient included immunohistochemical probes to detect c-Myc, EZH2, Sirt1 and CXCR4 protein analytes. Biomedical analytics schematically showed the interactions of these analytes with the morphoproteomic findings and illustrated targeted therapeutic options.
RESULTS: Representative sections of this patient\'s tumor displayed plasmalemmal expression for CXCR4 and nuclear immunopositivity for c-Myc, EZH2, and Sirt1. This coincided with their block in differentiation and their proliferative state with progression into the mitotic phase. Biomedical analytics integrated the morphoproteomic findings with the undifferentiated and proliferative state of SNUC and depicted pharmacogenomic and other related factors that target the c-Myc, EZH2, Sirt1 and CXCR4 pathways.
CONCLUSIONS: Morphoproteomics and biomedical analytics have identified c-Myc, EZH2, Sirt1 and CXCR4 pathways that collectively could contribute to the block in differentiation and increase the propensity for recurrence and metastasis in SNUC. This suggests that combinatorial therapies modulating these pathways could be used in a maintenance mode to minimize the risk of recurrent disease.