The study presents a comprehensive molecular characterization of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. It identifies four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV)-positive, microsatellite instability (MSI), genomically stable, and chromosomally unstable (CIN). Each subtype is characterized by distinct molecular features, such as EBV-positive tumors showing recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (PD-L1), and PDCDILG2 (PD-L2); MSI tumors with elevated mutation rates and hypermethylation; genomically stable tumors enriched for diffuse histology and mutations in RHOA or RHO-family GTPase-activating proteins; and CIN tumors with aneuploidy and focal amplification of receptor tyrosine kinases. These subtypes provide a framework for patient stratification and targeted therapy development. The study also highlights the clinical and histological characteristics of these subtypes, including the enrichment of diffuse histology in genomically stable tumors, and the association of CIN tumors with the gastroesophageal junction/cardia. The molecular subtypes are associated with different patient demographics, such as the younger age of diagnosis in genomically stable tumors and the higher prevalence of female patients in MSI tumors. The study further identifies recurrent somatic mutations, including PIK3CA, ARID1A, and BCOR, and highlights the role of RHOA mutations in genomically stable tumors. It also identifies structural genomic alterations, such as gene fusions involving CLDN18 and ARHGAP26, which may contribute to the invasive phenotype of diffuse gastric cancer. The study also explores gene expression and proteomic data, revealing distinct expression patterns across the molecular subtypes. It identifies potential therapeutic targets, including the PI3-kinase pathway, RAS signaling, and PD-L1/PD-L2, which may be relevant for targeted therapies in specific subtypes. Overall, the study provides a detailed molecular classification of gastric cancer, which may serve as a valuable tool for guiding patient therapy and clinical trials. The findings highlight the importance of molecular subtyping in gastric cancer and suggest that targeted therapies may be more effective in specific subtypes. The study also underscores the need for further research to validate these findings and explore their clinical implications.The study presents a comprehensive molecular characterization of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. It identifies four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV)-positive, microsatellite instability (MSI), genomically stable, and chromosomally unstable (CIN). Each subtype is characterized by distinct molecular features, such as EBV-positive tumors showing recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (PD-L1), and PDCDILG2 (PD-L2); MSI tumors with elevated mutation rates and hypermethylation; genomically stable tumors enriched for diffuse histology and mutations in RHOA or RHO-family GTPase-activating proteins; and CIN tumors with aneuploidy and focal amplification of receptor tyrosine kinases. These subtypes provide a framework for patient stratification and targeted therapy development. The study also highlights the clinical and histological characteristics of these subtypes, including the enrichment of diffuse histology in genomically stable tumors, and the association of CIN tumors with the gastroesophageal junction/cardia. The molecular subtypes are associated with different patient demographics, such as the younger age of diagnosis in genomically stable tumors and the higher prevalence of female patients in MSI tumors. The study further identifies recurrent somatic mutations, including PIK3CA, ARID1A, and BCOR, and highlights the role of RHOA mutations in genomically stable tumors. It also identifies structural genomic alterations, such as gene fusions involving CLDN18 and ARHGAP26, which may contribute to the invasive phenotype of diffuse gastric cancer. The study also explores gene expression and proteomic data, revealing distinct expression patterns across the molecular subtypes. It identifies potential therapeutic targets, including the PI3-kinase pathway, RAS signaling, and PD-L1/PD-L2, which may be relevant for targeted therapies in specific subtypes. Overall, the study provides a detailed molecular classification of gastric cancer, which may serve as a valuable tool for guiding patient therapy and clinical trials. The findings highlight the importance of molecular subtyping in gastric cancer and suggest that targeted therapies may be more effective in specific subtypes. The study also underscores the need for further research to validate these findings and explore their clinical implications.