••Evaluate characteristics2Sequence27 genesHERPACCCases 1,433Controls 5,997•Clarify gene-environmental interaction•Estimate cumulative riskSequence27 genesBBJCases 10,426 Controls 38,153Identify risk genesH. pylori infection combines with pathogenic genetic variants to increase gastric cancer risk by nearly 10-fold compared to genetics alone – a finding IMS researchers hope will empower and reduce anxiety among carriers.Like the vast majority of diseases, gastric cancer arises from the complex interplay between genetic and environ-mental factors. The disease is associated with pathogenic variants in several genes and modifiable factors such as smoking, salt intake, and infection with Helicobacter pylori bacteria. How these factors interact to impact gastric can-cer risk, however, remains a mystery.To address this knowledge gap, Yukihide Momozawa, Team Leader of the Laboratory for Genotyping Develop-ment at IMS, and his team focused on H. pylori infection as a key environmental factor in gastric cancer.“Gastric cancer is a particularly big problem in East Asia, where the high incidence rate is attributed to the variation of H. pylori, which is highly toxic,” explained Yoshiaki Usui, a Special Postdoctoral Researcher in Momo-zawa’s team and first author on the paper published in The New England Journal of Medicine.In their study, the researchers designed a large-scale genetic study taking advantage of the strengths of two cohorts: the large sample size from throughout Japan in BioBank Japan (BBJ) and the epidemiological design and availability of environmental factors, including H. pylori infection status, in the Hospital-based Epidemiologic Re-search Program at Aichi Cancer Center (HERPACC).By analyzing genetic variants in over 50,000 individuals with gastric cancer and controls, the researchers identified 27 cancer-predisposing genes in the BBJ and HERPACC cohorts. Further analysis of the BBJ population identified nine risk genes, including CDH1 – a well-known heredi-tary gastric cancer risk gene. Interestingly, the other eight genes occurred at higher frequency than CDH1.“These findings suggest that more people than expected had predisposition to gastric cancer,” remarked Usui, add-ing that the eight additional genes should be considered in guidelines for disease management.Importantly, analysis of the HERPACC population revealed a surprisingly substantial additive interaction be-tween H. pylori infection and pathogenic variants for gas-tric cancer risk. Compared to a less than 5% risk in those aged 85 years with or without genetic risk factors and lack-ing H. pylori infection, the presence of infection increased the risk to 14.4% in non-carriers of risk genes and a whop-ping 45.5% in carriers.Interestingly, no interaction was observed between pathogenic variants and other environmental factors such as smoking and salt intake, suggesting that clinicians and individuals with pathogenic variants should mostly focus on H. pylori infection status to reduce gastric cancer risk.“This study is a great example that genetic risk is not everything,” commented Momozawa, who acknowledged that genetic studies can induce anxiety in carriers. “In this case, those with pathogenic variants can get checked and treated for H. pylori infection to dramatically decrease their gastric cancer risk.”Mechanistically, the team showed that four of the nine identified risk genes have roles in homologous recombina-tion. This, together with H. pylori’s known action in dam-aging DNA and its repair processes, is a significant one-two punch that accounts for the higher gastric cancer risk.However, the researchers note that, due to the unique variation of H. pylori in East Asia, the interaction with ge-netic variants may be different in other parts of the world and should be investigated. This, Momozawa concluded, highlights the importance of local and regional studies to enable population-specific treatment.Figure: Large-scale genetic analysis of the Japa-nese population demonstrates a 45% risk of gas-tric cancer in the presence of both pathogenic variants and H. pylori infectionAnalysis of genetic variants in over 50,000 individuals with gastric cancer and controls was carefully designed to take advantage of the large dataset from throughout Japan of BioBank Japan (BBJ) and the epidemiologi-cal design and availability of environmental factors, including H. pylori infection status, in the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). The analysis identified nine risk genes for gastric cancer and ultimately uncovered a greater than 45% risk of gastric cancer in individuals with combined genetic factors and H. pylori infection, compared to just 5% in those without infection.Original paper:Usui Y, Taniyama Y, Endo M, Koyanagi Y, Kasugai Y, Oze I, Ito H, Imoto I, Tanaka T, Tajika M, Niwa Y, Iwasaki Y, Aoi T, Hakozaki N, Takata S, Suzuki K, Terao C, Hatakeyama M, Hirata M, Sugano K, Yoshida T, Kamatani Y, Nakagawa H, Matsuda K, Murakami Y, Spurdle A, Mat-suo K, Momozawa Y. Helicobacter pylori, homologous recombina-tion genes and gastric cancer. N Engl J Med 388, 1181-1190 (2023)Yukihide MomozawaGenes and the environment: A one-two punch in gastric cancer
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