Gene Expression Signature in Sinonasal Undifferentiated Carcinoma

Background: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer that arises in the nasal cavity and paranasal sinuses. Despite aggressive multimodal therapy the prognosis remains poor, and the median survival time is less than 18 months. To better understand the biological features of SNUC and help identify therapeutic targets in SNUC, gene expression analysis is crucial. Additionally, the exact histogenesis of SNUC is unclear and it remains controversial whether SNUC is a distinct pathologic entity with poorly differentiated neuroendocrine features or it represents an undifferentiated tumor of squamous lineage. Currently there are no reliable histopathologic markers to distinguish SNUC from undifferentiated sinonasal squamous cell carcinoma (SNSCC). Therefore, identifying new diagnostic molecular markers for SNUC is required. However, because of rarity of this tumor expression studies in SNUC have not been performed so far. To identify gene expression signature of SNUC, we employed the HTG EdgeSeq system which allows us to use small formalin-fixed paraffin-embedded (FFPE).

Materials and Methods: FFPE samples from treatment-naive 15 SNUC patients and 6 SNSCC patients treated at MD Anderson Cancer Center between 1999 to 2016 were used in this study. Gene expression analysis was performed on an HTG EdgeSeq Oncology Biomarker Panel. Unsupervised cluster analysis and Mann Whitney test were performed using JMP software and MetaboAnalyst 3.0 (www.metaboanalyst.ca), previously. Pathway analysis was performed using Ingenuity Pathway Analysis and Database for Annotation Visualization and Integrated Discovery v6.7 (david.ncifcrf.gov).

Results: Unsupervised cluster analysis divided the patients into two groups; one group had only SNUCs and the other one had mainly SNSCCs. Around 500 genes showed different expression patterns in SNUC when compared with SNSCC tumor specimens. (Mann Whitney test; p < 0.05). Pathway analysis revealed that several signaling pathways were either upregulated or downregulated in SNUC compared with SNSCC, including the P53 and DNA repair pathways.

Conclusions: Our study suggests that SNUC has different gene expression spectrum compared with SNSCC. Pathway analysis showed some significant signature signaling pathways in SNUC. This is the first report of comprehensive gene expression study in SNUC and reveals potential therapeutic targets and new prognostic markers.