SMARCB1-Deficient and SMARCB1-Retained Sinonasal Undifferentiated Carcinoma (SNUC) Subtypes are Genetically Distinct: A Pilot Study Using RNA Sequencing

 

Introduction: Sinonasal undifferentiated carcinoma (SNUC) has one of the worst survival outcomes among sinonasal malignancies. Recently, a novel molecular classification system based on SMARCB1 immunohistochemical staining pattern was described which showed that SMARCB1-deficient (SD) SNUC has a significantly worse prognosis in comparison to SMARCB1-retained (SR) SNUC. However, it is not known if the genetic profile of these tumors is distinct. The objective of this study was to compare the genetic profiles of SD and SR.

Methods: Formalin-fixed, paraffin-embedded (FFPE) SNUC tissue samples with predetermined SMARCB1 status (SR/SD) were selected. FFPE samples of normal sinonasal tissue from noncancer patients were utilized as control (C). High-throughput RNA sequence with the Illumina NextSeq 500 (sequencing platform) and R/Bioconductor DESeq2 package (for differential gene expression analysis; DGE) was used.

Results: Although SMARCB1 expression was detected in all samples, SD consistently lacked evidence of full-length transcript (most notably exon1/exon2 junctions) unlike SR and C. On analyzing the DGE, it was observed that all pairs of comparisons, SR versus C, SD versus C, tumor versus C, and SD versus SR, showed DGE. RNA sequence junction alignments spanning the SMARCB1 genomic region are shown in [Fig. 1]. Gene set enrichment analysis was used to detect differentially regulated “hallmark” gene signatures that represent well-defined biological states and processes ([Table 1]). TGF-β, NOTCH, and IL-6 JAK-STAT 3 signaling were the most common hallmark genes that were downregulated in SD versus SR. In comparison to control specimens, MYC targets and KRAS signaling were downregulated in SD; IL2 STAT5 signaling, INF-α, and p53 pathway were downregulated in SR; and p53, TGF-β, and mitotic spindle were downregulated in SNUC (SR and SD).

Conclusion: This is the first study to identify the genetic basis for the two clinicopathological subtypes, SD and SR SNUCs. Both subtypes were clearly noted to be genetically distinct which likely explains the differential prognosis. The various novel hallmark genes described could be potential targets for therapeutic agents. Further detailed gene analysis is underway.

Funding

The authors acknowledge funding from NASBS research grant 2020.

Publication History

Article published online:
15 February 2022

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