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

CDH1

Germline pathogenic or likely pathogenic variants, notably in CDH1, associated with an increased risk of gastric cancer diagnosed at age 50 or younger, with an exploratory signal for BRCA1 and RAD51D

Early-onset gastric cancer (EOGC), diagnosed at age 50 or younger, has clinicopathological and epidemiological characteristics distinct from late-onset gastric cancer, suggesting a stronger contribution of genetic susceptibility, yet the genes involved and their roles remain uncertain. This systematic review and meta-analysis, conducted following PRISMA guidelines in PubMed and Web of Science, included observational studies assessing germline variants in gastric adenocarcinoma: twenty studies comprising 4,289 patients met the inclusion criteria, of which six (2,009 patients) were included in the meta-analysis. Pathogenic or likely pathogenic CDH1 variants were associated with an increased risk of EOGC (RR 1.34; 95% CI 1.19-1.52; p < 0.0001), and BRCA1 and RAD51D showed a similar but exploratory association (RR 1.35; 95% CI 1.15-1.58; p = 0.0002 for both), with no significant association for other genes. The authors confirm CDH1 as an established contributor to EOGC, put forward preliminary evidence for BRCA1 and RAD51D, and conclude that the genetic landscape of EOGC remains poorly defined and that larger studies are needed.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The CDH1 result confirms what was already known and is the only one that holds up: RR 1.34 (95% CI 1.19-1.52) across six studies and 2,009 patients; the abstract does not specify the reference group, so this RR should not be read as a penetrance. For BRCA1 and RAD51D the values are strictly identical (RR 1.35; p = 0.0002 for both), which, together with the small number of pooled studies, argues for treating them as an exploratory signal, as the authors do, and not as a reason to widen testing. The authors themselves conclude that the genetic landscape of early-onset gastric cancer remains poorly defined, which is the honest way to sum up a meta-analysis in which only 6 of 20 studies were pooled.

Analysis by Dr Thibaut Benquey