Evolving Molecular Subtypes of Gastric Cancer: From Past Classifications to Present Consensus and Future Directions for Precision Therapy

Gastric cancer is a biologically heterogeneous disease. The advent of high-throughput multi-omic technologies has revolutionized our understanding of gastric cancer by deconstructing this heterogeneous entity into distinct and more homogeneous molecular subtypes. Early classifications based on gene expression, methylation, and histology have laid the groundwork for multi-omic frameworks proposed by The Cancer Genome Atlas and Asian Cancer Research Group, which established the foundation of modern molecular taxonomy. Subsequent integrative efforts, particularly the Consensus Genomic Subtypes (Super 6) model, have unified this collected information into clinically relevant subtypes that bridge prognostic stratification with treatment strategies. Established biomarkers such as human epidermal growth factor receptor 2 amplification, microsatellite instability, and programmed death-ligand 1 expression are now used clinically to guide treatment with targeted agents and immune checkpoint inhibitors. Emerging single-cell and spatial transcriptomic analyses have further refined this landscape by deconstructing tumor microenvironments and potential evolutionary trajectories associated with disease progression. This review examines the evolution of molecular classification systems for gastric cancer, highlights current consensus frameworks, and discusses how subtype-based stratification will transform clinical trial design and enable biomarker-driven precision therapy.