Genetic risk factors in Early-Onset Gastric Cancer: A systematic review and meta-analysis

Early-onset gastric cancer (EOGC), defined as gastric cancer (GC) diagnosed at a young age, has distinct clinicopathological and epidemiological characteristics compared to late-onset GC, suggesting a stronger contribution of genetic susceptibility. However, the specific genes involved and their roles remain uncertain. This systematic review and meta-analysis aimed to evaluate germline risk factors and their association with EOGC.

A systematic literature search was conducted in PubMed and Web of Science databases, following PRISMA guidelines. Observational studies assessing germline variants in gastric adenocarcinoma were included. EOGC was defined as a diagnosis at 50 years or younger. Pathogenic or likely pathogenic (P/LP) variants, variants of uncertain significance, and polymorphisms were considered. Random-effects models were used to estimate pooled risk ratios (RRs) with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran's Q test and the I² statistic.

Twenty studies comprising 4289 patients with GC met the inclusion criteria, of which six (2009 patients) were included in the meta-analysis. P/LP variants in CDH1 (RR=1.34; 95% CI=1.19-1.52; p < 0.0001), were associated with increased EOGC risk. BRCA1and RAD51D showed a similar, though exploratory, association (RR=1.35; 95% CI=1.15-1.58; p = 0.0002 for both). No significant associations were identified for other genes.

CDH1 is a well-established contributor to early-onset gastric cancer, and this association was confirmed in our study. We also found preliminary evidence associating P/LP germline variants in BRCA1 and RAD51D with increased EOGC risk, consistent with the literature. Overall, however, the genetic landscape of EOGC remains poorly defined, and larger studies are needed to clarify these associations.