CNV-mediated dysregulation of the ceRNA network mechanism revealed heterogeneity in diffuse and intestinal gastric cancers.

Background: Gastric cancer (GC) is a highly heterogeneous tumour with high morbidity. Approximately 95% of GC cases are gastric adenocarcinomas, which are further categorized into two predominant subtypes: diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC). These subtypes exhibit distinct pathophysiological and molecular characteristics, reflecting their unique tumorigenic mechanisms.

Method: In this study, we employed a comprehensive approach to identify driver genes associated with DGC and IGC by focusing on copy number variation (CNV) genes within the competing endogenous RNA (ceRNA) network. The influence of driver CNV genes on the molecular, cellular, and clinical differences between DGC and IGC was subsequently analysed. Finally, therapeutic strategies for DGC and IGC were evaluated based on the status and functional pathways of the driver CNV genes.

Results: A total of 17 and 22 driver CNV genes were identified in DGC and IGC, respectively. These genes drive subtype differences through the ceRNA network, resulting in alterations in the tumour microenvironment (TME). Based on these differences, personalized treatment strategies for DGC or IGC could be developed. Immune checkpoint inhibitors may be an effective treatment option in IGC. Additionally, DGC patients with homozygous deletion of PPIF might benefit from adjuvant chemotherapy, whereas those with high-level amplification of MTAP could respond to targeted therapy.

Conclusion: Driver CNV genes were identified to reveal the underlying cause of heterogeneity in DGC and IGC. Furthermore, specific driver CNV genes were identified as potential therapeutic targets, facilitating personalized treatment.