Systematic review of gastric cancer-associated genetic variants, gene-based meta-analysis, and gene-level functional analysis to identify candidate genes for drug development

Objective: Despite being a powerful tool to identify novel variants, genome-wide association studies (GWAS) are not sufficient to explain the biological function of variants. In this study, we aimed to elucidate at the gene level the biological mechanisms involved in gastric cancer (GC) development and to identify candidate drug target genes. Materials and methods: We conducted a systematic review for GWAS on GC following the PRISMA guidelines. Single nucleotide polymorphism (SNP)-level meta-analysis and gene-based analysis (GBA) were performed to identify SNPs and genes significantly associated with GC. Expression quantitative trait loci (eQTL), disease network, pathway enrichment, gene ontology, gene-drug, and chemical interaction analyses were conducted to elucidate the function of the genes identified by GBA. Results: A review of GWAS on GC identified 226 SNPs located in 91 genes. In the comprehensive GBA, 44 genes associated with GC were identified, among which 12 genes (THBS3, GBAP1, KRTCAP2, TRIM46, HCN3, MUC1, DAP3, EFNA1, MTX1, PRKAA1, PSCA, and ABO) were eQTL. Using disease network and pathway analyses, we identified that PRKAA, THBS3, and EFNA1 were significantly associated with the PI3K-Alt-mTOR-signaling pathway, which is involved in various oncogenic processes, and that MUC1 acts as a regulator in both the PI3K-Alt-mTOR and P53 signaling pathways. Furthermore, RPKAA1 had the highest number of interactions with drugs and chemicals. Conclusion: Our study suggests that PRKAA1, a gene in the PI3K-Alt-mTOR-signaling pathway, could be a potential target gene for drug development associated with GC in the future. Systematic Review Registration: website, identifier registration number.