Subtype-Specific Noncoding Ribonucleic Acid Signatures in Gastric Cancer: Insights from The Cancer Genome Atlas-Based Classification

Abstract

Gastric cancer (GC) is the fifth most common malignancy and one of the leading causes of cancer-related death worldwide. Its histological and molecular heterogeneity make it particularly challenging to manage. The Cancer Genome Atlas classifies GC into four molecular subtypes: Epstein–Barr virus-associated GC (EBVaGC), microsatellite instability-high (MSI-H), chromosomal instability (CIN), and genomic stability (GS), each of which has distinct genetic and epigenetic characteristics. Among this biomarker diversity, non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs play a key role in diagnosis, prognosis, and targeted therapy. For instance, the EBVaGC subtype features PIK3CA mutations and hypermethylation of tumor suppressor genes such as CDKN2A, alongside ncRNAs such as EBV-encoded RNAs and H19 that enhance immunogenicity and response to programmed death-1/programmed death-ligand 1 inhibitors. MSI-H-GC is characterized by high mutational load and DNA mismatch repair defects, and ncRNAs such as MIR99AHG serve as prognostic and immunomodulatory markers. CIN-GC, the most common subtype, is associated with amplification of genes such as ERBB2/HER2 (human epidermal growth factor receptor 2) and ncRNAs such as miR-22 and TERRA, which exacerbate CIN and are linked to a poor prognosis may be amenable to HER2-targeted therapies. GS-GC is characterized by RHOA and CDH1 mutations and epithelial-to-mesenchymal transition (EMT) features, where ncRNAs such as HOX antisense intergenic RNA, ZFAS1, and Linc00152 affect invasion and metastasis by regulating EMT. Through interactions with miRNAs and signaling pathways, these ncRNAs not only influence prognosis but also represent novel therapeutic targets. Integrating multiomics approaches and developing ncRNA-based biomarker panels are essential for advancing precision medicine in GC.