Aims/Background
Perineural invasion (PNI) is an independent prognostic indicator across multiple malignancies, yet molecular profiling in gastroesophageal cancer remains limited. We aimed to identify differentially expressed genes and biological pathways associated with PNI in gastroesophageal adenocarcinomas.
Methods
Gene expression profiling was performed using the NanoString nCounter Cancer Progression panel (770 genes, 35 pathways). Following quality-control exclusion, 31 gastroesophageal adenocarcinoma samples (10 PNI-positive, 21 PNI-negative) were utilised. Pathway scores were derived via principal component analysis of standardised gene expression with comparisons using the Mann-Whitney U test with Benjamini-Hochberg correction (false discovery rate [FDR]< 0.05); gene-level differential expression was assessed by negative binomial regression.
Results
Pathway-level analysis revealed a distinct transcriptional gradient between PNI groups. Twelve pathways exhibited significant upregulation in PNI-positive samples, with the strongest associations for angiogenesis, matrix-metalloproteinase (MMP) remodelling, and basement membrane integrity (Cohen’s d = 1.12–1.33). Differential expression analysis identified 147 significantly altered genes (141 upregulated, 6 downregulated), reflecting transcriptional asymmetry. The 10 most upregulated genes included GREM1 (log2 fold change (log₂FC)= 3.93), MGP(log₂FC= 4.15), ABI3BP (log₂FC= 3.49), THBS4 (log₂FC= 3.91), DCN (log₂FC= 2.81), FBLN1 (log₂FC= 2.85), BAG2(log₂FC= 3.60), MYLK (log₂FC= 3.71), SPARCL1 (log₂FC= 3.45), and JAM2 (log₂FC= 2.90).
Conclusion
Gastroesophageal cancers with upregulation of ECM remodelling, EMT, sprouting angiogenesis, and neural microenvironment genes are associated with PNI. GREM1 and MGP were significantly upregulated and warrant prospective evaluation. The upregulated genes converge on extracellular matrix remodelling and TGF-B signalling indicating stroma reprogramming and may facilitate tumour-nerve interaction.