mRNA profiles to identify metaphase, histone, and cancer testis antigen gene overexpression in metastatic GEP-NETs: An ORIEN analysis.

Abstract

e16313 Background: Well-differentiated GEP-NETs comprise a heterogenous group of malignancies with variable behavior. While existing grading structures attempt to predict these behaviors, significant variability remains. The ORIEN database contains complementary clinical, genomic, and transcriptomic profiling, providing a novel source for correlating molecular data with clinical characteristics. Methods: mRNA expression profiles were assessed for correlation the presence (M1) or absence (M0) of metastatic disease at diagnosis. The workflow consisted of: (1) Data preparation: RSEM gene expression data were processed, quality-controlled, and mapped to clinical metadata. (2) Differential gene expression: DESeq2 was used to identify significantly differentially expressed genes (FDR < 0.05). (3) Pathway enrichment analysis: Gene Ontology (GO), KEGG, and Reactome enrichment analyses were performed on all differentially expressed genes to identify biological pathways associated with metastatic status. Results: Across all GEP-NETs, 112 genes had significantly different expression levels for M1 (n = 5) vs. M0 (n = 24) stage, including 35 genes expressed at higher levels in M1 disease. In analysis limited to pNETs, 708 genes showed significantly different expression levels between M1 (n = 3) and M0 (n = 20) stages, including 155 genes expressed at higher levels in in M1 disease. In both the entire GEP-NET cohort and pNET subgroup analysis, the most frequently overexpressed Reactome pathways associated with M1 stage were related to the regulation of metaphase transition and DNA-protein (histone) interactions. Cancer testis antigen (CTA) genes were also frequently upregulated (Table 1). Conclusions: Differential mRNA expression data provides a novel means for better characterizing the molecular underpinnings of GEP-NETs. Specifically, cell cycle, histone-related, and CTA gene expression profiles may provide actionable findings on which to base downstream drug development for the prevention and/or treatment of metastatic disease. Most upregulated mRNA profiles by magnitude in metastatic GEP-NETs. Gene Log 2 Fold ∆ a Description / Function GAGE2A 7.41 CTA, chromatin regulator, anti-apoptosis RNF17 5.89 CTA, DNA damage response GTSF1 5.76 CTA, DNA methylation, retrotransposon regulation NBEAP1 5.19 Also called BCL8, little known normal physiologic function ORM1 4.53 Acute phase reactant, angiogenesis, immune evasion HIST2H3C 4.18 Histone H3 regulation, chromatin regulator LYZ 4.12 Lysozyme production, TME inflammation, immune evasion PBK 4.02 CTA, cell cycle regulation, histone phosphorylation, anti-apoptosis HIST2H3A 3.71 Histone H3 regulation, chromatin regulator a All p-values <0.0001.