Identification of novel biomarkers for gastric adenocarcinoma through two-sample Mendelian randomization analysis of the human plasma proteome

Papillary gastric adenocarcinoma (PGC), a histological subtype of gastric cancer (GC), is characterized by malignant potential and poor prognosis. Therefore, identifying novel biomarkers is urgently needed to enhance PGC diagnosis and treatment outcomes. This study utilized two-sample Mendelian randomization (MR) to explore potential causal relationships between human blood plasma proteins and GC. Heterogeneity testing, pleiotropy assessment, and directionality analyses were performed to evaluate identified plasma proteins. Additionally, pathway enrichment analysis was conducted to elucidate the molecular mechanisms underlying the causal associations between plasma proteins and GC development. MR analysis of 4,907 plasma proteins related to GC risk identified 90 proteins with potential causal relationships. The findings revealed that DNAJB9, CHCHD10, and suppressor of cytokine signaling 3 exhibited protective effects against GC, while Syntaxin-8, alcohol dehydrogenase 7, and UDP-glucose 4-epimerase were associated with increased GC risk at the genetic level. In the present study, the six plasma proteins identified through comprehensive MR analysis may serve as potential biomarkers for GC, offering new insights for future molecular diagnosis and therapeutic strategies.