Genomic Characterization of Sinonasal Undifferentiated Carcinoma

Background: Sinonasal undifferentiated carcinoma (SNUC), 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 develop new therapies, molecular profiling of SNUC is essential. However, our previous study failed to identify hot spot mutations within well-studied 12 oncogenes or tumor suppressor genes in 13 SNUC patient samples. To examine wider genomic alterations in SNUC, we performed whole genome sequencing and genome wide SNP analysis on a recently established SNUC cell line.

Materials and Methods: Genomic DNA isolated from the MDA8788–6 SNUC cell line. This cell line was established from a patient with T4N0M0 SNUC of the right maxillary sinus in our cancer center. Genomic DNA from fibroblasts derived from the same patient served as the reference DNA. Genome sequencing was performed to 60x coverage on an Illumina sequencing machine. SNP analysis was conducted on an Affimetrix Genome-Wide Human SNP6.0 array.

Results: Deletion of putative tumor suppressors such as fragile histidine traid (FHIT) (3p14.2) and, cyclin-dependent kinase inhibitor 3 (CDKN3) (14q22.2) were observed; Additionally, epidermal growth factor receptor 2 (ERBB2) (17q12, presented last year in this meeting) and transforming growth factor β-1 (TGFB1) (19q13.2) were found to be highly amplified. We also identified potential mutations in tumor suppressor genes including TP53. Based on signal pathway analysis, these mutations and amplification were integrated to 3 major pathways of dysregulation; HER2, TGF β and WNT signal.

Conclusions: Our study suggests that SNUC has complicated biology caused by alteration of multiple signaling pathways. To the best of our knowledge, this is the first report of genomic analysis of SNUC. Our result is a first step toward developing molecular targeted therapy in this deadly disease.