Abstract 7505: Comprehensive in-silico molecular analysis of early-onset gastric cancer identifies novel genes implicated in disease characterization and progression

Abstract Gastric cancer, a prevalent and fatal form of cancer worldwide, is manifested at different age ranges during the lifespan. Approximately one-third of newly diagnosed gastric cancer cases are early onset gastric cancer (EO-GC), which affects individuals under the age of 50. EO-GC tends to be more aggressive than late-onset gastric cancer (L-GC), with a faster and multifocal disease progression. Moreover, EO-GC is associated with early metastatic disease. Recent research has underscored the need for a deeper understanding of EO-GC that promotes therapeutic approaches specific to EO-GC. These characteristics emphasize the need to understand their differential molecular characteristics deeply. We analyzed The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) transcriptomic expression data as a proxy to understand if age may be positioned as a variable associated with a specific gene expression pattern in gastric cancer. Using transcriptomic and clinical data, we performed a comprehensive bioinformatic analysis to explore molecular differences between EO-GC (n = 32) and L-GC (n = 345). Principal component analysis (PCA) revealed distinct transcriptomic clusters separating EO-GC and L-GC cases, particularly when categorized by decades, highlighting their molecular divergence. Next, we performed differential gene expression analysis (DGEA) using the ‘DESeq2’ and ‘edgeR’ R packages, identifying several significant genes that distinguish EO-GC from L-GC. Among these, KLHL4, MAGEL2, RNLS, and CYP8B1 were upregulated in EO-GC, while CLDN6, MIOX, PNMA5, and ACTL8 were downregulated. Consequently, we performed a functional analysis of differentially expressed EO-GC genes related to cytoskeleton regulation, cell adhesion, and metabolism pathways, which may contribute to its aggressive phenotype. Furthermore, some EO-GC genes were associated with poorer survival outcomes. Last, we observed that the DNA methylation score was higher for EO-GC cases. In conclusion, our findings highlight the critical role of differential genetic and epigenetic landscapes of EO-GC and propose these molecular features for its diagnosis and prognostic evaluation. These insights could inform the development of personalized therapies to improve outcomes for younger GC patients. Citation Format: Fernan Gomez-Valenzuela, Ian Silva, Ignacio Nicolás Retamal, Javiera Garrido, Benjamín García-Bloj, Tomás De Mayo Glasser, Matías Muñoz-Medel, Juan Alejandro Godoy, Marcelo Garrido. Comprehensive in-silico molecular analysis of early-onset gastric cancer identifies novel genes implicated in disease characterization and progression [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 7505.