Abstract 7474: Comprehensive multi-omics characterization of gastric cancers with proteogenomic insights

Abstract Gastric cancers are one of the leading causes of cancer-related mortality worldwide. Characterized by high tumor heterogeneity, the treatment of gastric cancers remains challenging. Prior attempts to elucidate the tumor heterogeneity of gastric cancers have included subtyping it into differing clinical and molecular subtypes. For example, the main histological type, adenocarcinoma, has intestinal and diffuse subtypes. At the genomic level, gastric cancers are classified as either Epstein-Barr virus (EBV), microsatellite instability (MSI), chromosomal instability (CIN), or genomically stable (GS). Transcriptomic subtyping has further revealed subtype and clinical prognosis relationships: MSI, microsatellite-stable microsatellite stable with epithelial-to-mesenchymal transition phenotype (MSS/EMT) (poor prognosis), and MSS/TP53 active or inactive (intermediate prognosis). However, these subtypes are still poorly understood at the functional level. To address this gap, the Clinical Proteomics Tumor Analysis Consortium (CPTAC) conducted a comprehensive multi-omic characterization of 159 gastric tumors and 31 normal adjacent tissues. Moving beyond conventional genomic and transcriptomic analyses, we employed a novel multi-omics approach that encompasses the proteome, phosphoproteome, glycoproteome, metabolome, and additional “omes” such as ubiquitinome, acetylome, and protein-protein interactome. In addition, to better understand the unique role of the microbiota in gastric cancers, we integrated the entire microbiome genome and transcriptome data into the whole analysis. By combining these 12 layers of data and microbiome analysis together, our study provides unprecedented proteogenomic insights, advancing our understanding of the molecular mechanisms of gastric cancer oncogenesis and aiding in the development of novel precision oncologist therapies. In this study, we classified gastric cancers by molecular and clinical subtypes, revealing both shared and subtype-specific biological features at the multi-omic level. We highlight the associations of post-translational modification (PTM) alterations to immune and metabolic pathways. Proteogenomic analysis uncovered promising new surface targets and potential biomarkers for existing targeted therapies. Further in-depth analyses of PTMs and protein-protein interactions have uncovered insights into intracellular signaling pathways and PTM crosstalk with therapeutic potential. Additionally, the impact of microbiome on immune responses and PTM patterns underscores the interplay between microbiota and cancer phenotypes, providing valuable insights for advancing precision medicine in gastric cancers. Overall, our study provides the most comprehensive multi-omics atlas for gastric cancers, offering deep insights into its cancer biology and molecular heterogeneity. Citation Format: Lindsey K. Olsen, Yuefan Wang, Hui Zhang, Bing Zhang, Clinical Proteomic Tumor Analysis Consortium (CPTAC). Comprehensive multi-omics characterization of gastric cancers with proteogenomic insights [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7474.