Genetic Analysis of Sinonasal Undifferentiated Carcinoma Discovers Recurrent SWI/SNF Alterations and a novel PGAP3-SRPK1 Fusion Gene

Background: Sinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown. Methods: : We evaluate survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We perform exome sequencing to characterize a series of SMARCB1 wild type tumors and cell line including identification of high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA was utilized for validation of a novel PGAP3-SRPK1 gene fusion. Results: : We discover recurrent aberrations to the SWI/SNF and FAT gene families. We also validate a novel PGAP3 - SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling. Conclusion: Collectively, these data demonstrate recurrent alterations in the SWI/SNF and FAT gene families and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.