Synergistic effect of gastric microbiome and host genetic factor predispose to gastric cancer

OBJECTIVE: Complex interaction between host genetic and environmental factors has a role in Helicobacter pylori (H. pylori)-related gastric tumorigenesis, while involvement of non-Helicobacter pylori gastric microbiome may be also relevant to this process. We aimed to evaluate whether combining the non-Helicobacter pylori gastric microbiome signatures and the gastric cancer (GC) predisposing genetic factors (PSCA rs2294008 and MUC1 rs4072037 polymorphisms) stratify a high GC risk subpopulation in a Japanese cohort. METHODS: In 620 subjects including 219 GC patients and 410 non-cancers, microbiome-based GC risk was defined as the gastric microbiome signatures of 47 GC-predisposing bacteria. Genetic risk of GC was also defined as the presence of PSCA rs2294008 and MUC1 rs4072037 risk alleles. Adding effect of gastric microbiome and genetic factor was evaluated in relation to GC susceptibility, histological degree of gastritis and somatic changes in the gastric mucosa including DNA methylation and telomere shortening. RESULTS: Individuals possessing the risk of both microbiome and genotype showed significant risk for developing GC with highest OR (odds ratio, e.g., OR = 23.55 in comparison with non-cancer) compared to individuals having risk microbiome or genotype alone (microbiome, OR = 11.16; genotype, OR = 2.76). The individuals having both risks also showed highest degrees of intestinal metaplasia and DNA methylation, and shortest telomere. CONCLUSIONS: Our findings suggested an existence of combined effect of host genetic factor and gastric microbiome predispose to gastric tumorigenesis, that can be used as the diagnostic tool to further stratify a high GC risk subpopulation.