Young-Onset Gastric Cancer: Clinical and Genetic Perspectives

Young-onset gastric cancer (YOGC) is an increasingly recognized subtype that challenges traditional assumptions about gastric cancer (GC) biology. Although the overall global incidence of GC continues to decline, the rising burden among individuals aged <40 years has reshaped clinical perceptions, highlighting YOGC as a distinct entity with unique drivers and unmet needs. It is frequently associated with diffuse-type histology and enrichment of genomically stable or microsatellite stable/epithelial-mesenchymal transition molecular subtypes, diverging from conventional late-onset diseases. Family history remains the strongest risk factor; however, most cases are sporadic, suggesting a multifactorial interplay between inherited susceptibility, environmental exposure, and early-life carcinogenic pathways. YOGC is also associated with a unique genetic and molecular profile with predominance of CDH1, RHOA, and CLDN18-ARHGAP alterations, aligned with low human epidermal growth factor 2 expression. Clinically, nonspecific symptoms and lack of screening recommendations often result in diagnosis at advanced stages. Thus, current treatment approaches largely mirror those designed for older patients. This review synthesizes evolving knowledge on the epidemiology, molecular and genetic landscape, and clinical behavior of YOGC. We emphasize opportunities to refine risk stratification, integrate hereditary cancer management, and adopt emerging tools, such as liquid biopsy, for early detection and disease monitoring. Ultimately, defining the biological foundations of YOGC may enable tailored interventions and improve prognosis in this increasingly relevant and understudied population.