Real-world clinicogenomic comparison of early- and average- onset gastric cancer

In recent decades, there has been an unprecedented rise in gastric cancer among younger individuals, contrasting with a decline among older individuals. However, the biological underpinnings of gastric cancer in younger individuals remain poorly understood. We described the clinicopathologic and genomic characteristics of early-onset gastric cancer (EOGC) compared to average-onset gastric cancer (AOGC). We analyzed 311 patients using the multi-institutional prospective Oncology Research Information Exchange Network (ORIEN) database to compare demographic, clinicopathologic, genomic, and survival outcomes between EOGC (<50 years; N=72) vs AOGC (>50 years N=239). Genomic, germline, and RNA sequencing data were analyzed and compared between the cohorts. Mutational and immune signatures were also processed. EOGC patients exhibited significantly higher rates of pain at diagnosis (53% vs 30% p=0.001 ), but not anemia or reflux. EOGC patients were more likely to present with stage III/IV disease (70% vs 45% p=0.006 ) and diffuse/signet ring histology (47% vs 16% p=0.002 ). Consequently, OS was decreased in the younger cohort (HR 1.52; p=0.03). Somatic mutational load was decreased in young patients. Significantly mutated genes in the entire cohort included CDH1 , ARID1A , TP53 , PIK3CA, but CDH1 was more frequently mutated in the EOGC cohort (40% vs 18% p=0.09 ). Significant differences in RNA expression were observed, with upregulated epithelial mesenchymal transition (EMT), myogenesis, and apical junction. Immune deconvolution revealed a predominance of M2 macrophages, mast cells, and CD4 + T cell subsets, but no differences between cohorts. Early-onset gastric cancer has unique clinical and genomic features. Pathway dysregulation in EOGC may contribute to tumorigenesis and therapy resistance. This study underscores the necessity for further research into novel therapies, biomarker discovery, and early detection methodologies in younger individuals.