Bioinformatic Analysis of lncRNA H19 Reveals Its Regulatory Networks and Clinical Relevance in Gastric Cancer

Background & Objectives: Gastric cancer (GC) continues to rank among the leading causes of cancer-related mortality worldwide, primarily because of late-stage diagnosis, marked molecular heterogeneity, and the emergence of therapeutic resistance. The long non-coding RNA (lncRNA) H19 has been recognized as an oncogene in multiple malignancies; however, its precise molecular mechanisms and clinical significance in GC remain incompletely understood. Materials & Methods: We conducted an integrative bioinformatics analysis of 431 TCGA-STAD samples, integrating somatic mutation, RNA-seq, and clinical datasets. The study examined mutational landscapes, tumor mutational burden (TMB), and distinct mutational signatures. Patients were classified according to H19 expression levels for subsequent differential expression, correlation, pathway enrichment, protein–protein interaction (PPI) network construction, and survival analyses. Results: The most frequent mutations were identified in TTN (51%), TP53 (46%), MUC16 (31%), ARID1A (27%), and LRP1B (27%). Six distinct mutational signatures were detected, reflecting processes associated with aging, mismatch repair deficiency, POLE-driven hypermutation, and prior chemotherapy exposure. Stratification based on H19 expression revealed 15,179 differentially expressed genes that were significantly enriched in pathways related to extracellular matrix organization, focal adhesion, and cell adhesion. H19 exhibited strong positive correlations with IGF2, TCF15, and miR-675, suggesting a potential competing endogenous RNA (ceRNA) function, and negative correlations with ATP4A and ATP4B, indicating possible disruption of parietal cell activity. The hub genes identified within the PPI network included GAPDH, COL1A1, TGFB1, and SIRT1. Conclusion: Collectively, these findings suggest that H19 acts as a pivotal regulator in GC by modulating ceRNA networks, promoting extracellular matrix remodeling, and influencing oncogenic signaling cascades. Although its independent prognostic significance has yet to be fully established, this comprehensive systems-level analysis provides valuable insights and lays the groundwork for future experimental and clinical studies exploring H19 as a potential diagnostic biomarker and therapeutic target.