Genetic analysis of sinonasal undifferentiated carcinoma discovers recurrent SWI/SNF alterations and a novel PGAP3-SRPK1 fusion gene

Abstract

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 evaluated 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 performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788–6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion. Results Overall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/− CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated 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 family as well as IDH, JAK/STAT, and PI3K pathways 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.

Methylation Drivers and Prognostic Implications in Sinonasal Poorly Differentiated Carcinomas

“…Recent studies of molecular profiling of PDSNCs have demonstrated frequent alterations of chromatin modulators, i.e., SWI/SNF subunits (SMARCB1, SMARCA2, SMARCA4, and ARID1A) or of proteins leading to CpG island methylator phenotype (CIMP) by inhibiting the TET-demethylation pathway (i.e., IDH2 ) [ 34 ]. Additionally, NUT gene rearrangements, leading to differentiation arrest through chromatin deregulation, are specific molecular markers of NUT carcinomas.…”

SMARCB1-Retained and SMARCB1-Deficient SNUC are Genetically Distinct: A Pilot Study Using RNA Sequencing

“…Based on the distinct clinical outcomes of this study it is imperative to understand the molecular basis of the two types of SNUC -SR-SNUC and SD-SNUC. Although there are a few studies [14][15][16] describing the molecular characteristics of SNUC, to our knowledge this is the first study comparing the genetic makeup of the two types of SNUC based on SMARCB1 status. This absence of SMARCB1 in some of the non-sinonasal cancer has been used as a molecular marker for targeted therapies in several clinical trials.…”

IDH2-Mutated Sinonasal Tumors: A Review

“…Mitotic figures are frequent, with a median of 37 mitoses/10 high-power fields 9. While nested growth pattern, large cells, prominent nucleoli, high mitotic count, and necrosis are consistent findings, there is no unique feature that is helpful to differentiate IDH2 -mutated from IDH2 wild-type tumors,4–6,9–12 thus, molecular and immunohistochemical studies are warranted.…”

“…Significant squamous or glandular differentiation hinders the diagnosis of SNUC. IST accounts for 20% to 88% of SNUC cases 4–6,9–12. IST with SNUC-like morphology ( IDH2 -SNUC) shows large, undifferentiated epithelial tumor cells, display open chromatic, cherry-red nucleoli, and a high N:C ratio 5 .…”

“…Next-generation sequencing (NGS) or Sanger sequencing will identify the hotspot mutation affecting amino acid R172 of the IDH2 gene. Reported mutations include R172S, R172T, R172G, and R172M (61%, 19%, 7%, and 3%, respectively) 4–6,9–13…”