<i>Helicobacter pylori</i>, Homologous-Recombination Genes, and Gastric Cancer.

Abstract

<i>Helicobacter pylori</i> infection is a well-known risk factor for gastric cancer. However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with <i>H. pylori</i> infection, on the risk of gastric cancer has not been widely evaluated. We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and <i>H. pylori</i> infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). Germline pathogenic variants in nine genes (<i>APC</i>, <i>ATM</i>, <i>BRCA1</i>, <i>BRCA2</i>, <i>CDH1</i>, <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, and <i>PALB2</i>) were associated with the risk of gastric cancer. We found an interaction between <i>H. pylori</i> infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval [CI], 2.22 to 29.81; P = 0.02). At 85 years of age, persons with <i>H. pylori</i> infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with <i>H. pylori</i> (45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to 16.6]). <i>H. pylori</i> infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.).