Molecular features of early- vs. late-onset gastric cancer: a systematic review and meta-analysis

Background: Early-onset gastric cancer (EOGC), diagnosed before the age of 50, exhibits distinct clinicopathological and molecular characteristics compared to late-onset gastric cancer (LOGC). However, the molecular landscape of EOGC remains incompletely defined. This study systematically reviews and meta-analyzes the molecular differences between EOGC and LOGC. Methods: A comprehensive literature search was conducted in PubMed, Embase, and Web of Science to identify studies comparing the molecular features between EOGC and LOGC. Meta-analyses were performed to assess differences in The Cancer Genome Atlas (TCGA) molecular subtypes, frequently mutated genes, key therapeutic biomarkers, and serum tumor markers. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and heterogeneity was evaluated via the I² statistic. Results: EOGC was associated with a significantly greater prevalence of the genomically stable (GS) subtype (OR = 1.71, 95% CI: 1.37–2.12) and a lower prevalence of the chromosomal instability (CIN) subtype (OR = 0.62, 95% CI: 0.50–0.77). CDH1 mutations were more common in EOGC (OR = 3.56, 95% CI: 2.94–4.31), whereas HER2 expression was significantly lower (OR = 0.55, 95% CI: 0.44–0.68). EOGC patients had a lower prevalence of deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) (OR = 0.25, 95% CI: 0.12–0.53) but higher PD-L1 expression (OR = 2.11, 95% CI: 1.26–3.54). Serum markers such as CEA (OR = 0.43, 95% CI: 0.36–0.51) and CA19-9 (OR = 0.70, 95% CI: 0.58–0.85) were also less frequently elevated in EOGC. Conclusion: EOGC constitutes a biologically distinct subset of gastric cancer, defined by unique genomic, immune, and serological profiles. These differences highlight the need for age-specific diagnostic and therapeutic strategies and emphasize the value of multiomics approaches to further elucidate the molecular basis of early-onset disease.