Gastric cancer is a significant global health problem, ranking as the fifth most common neoplasm and the fourth leading cause of cancer-related deaths worldwide. Helicobacter pylori infection has been classified as a group I carcinogen and is a well-established environmental risk factor for gastric cancer.
Despite the fact that more than half of the world population is affected by H. pylori infection, the age-standardized global incidence rate of cancer attributed to H. pylori infection is highest in East Asia. As a result, tailored surveillance and eradication of H. pylori are recommended as measures to control the incidence of gastric cancer.
Apart from H. pylori infection, germline pathogenic variants in cancer-predisposing genes are also significant factors in tailored surveillance and prevention of gastric cancer. For example, CDH1 is a risk gene for hereditary diffuse gastric cancer, and carriers of pathogenic variants in this gene are recommended for prophylactic gastrectomy.
Recently, germline pathogenic variants in BRCA1 and BRCA2 in the homologous-recombination genes have also been found to substantially increase the risk of gastric cancer. However, the identification of variants in these genes is not included in screening recommendations, except for CDH1.
A randomized controlled trial has shown that eradication of H. pylori reduces the incidence of gastric cancer, even in persons with a first-degree family history of gastric cancer. However, because a family history usually involves shared genetic and environmental factors, it remains unclear whether eradication is effective primarily in genetically susceptible persons or regardless of genetic status. As gene-environment interactions are associated with an excess risk of disease, an evaluation of pathogenic-variant carrier status and H. pylori infection status may be useful for risk stratification.
A recent study published in The New England Journal of Medicine has found that several genetic mutations, including CDH1, APC, ATM, MLH1, MSH2, MSH6, and PALB2, are associated with an increased risk of gastric cancer. The study, which was conducted in East Asia, also found that individuals with both a genetic mutation and an infection of H. pylori, a bacterium commonly found in the stomach, are at even greater risk for developing gastric cancer.
The study showed that individuals with a pathogenic variant in a homologous-recombination gene, who also had H. pylori infection, had a significantly higher risk of developing gastric cancer compared to those with only one of these risk factors. The researchers hypothesized that the DNA damage caused by H. pylori infection might contribute to gastric carcinogenesis and that the risk is increased in individuals with a reduced DNA damage-repair capacity due to damaging variants in homologous-recombination genes.
The study also found that the age of diagnosis for gastric cancer among pathogenic-variant carriers was younger than noncarriers. Furthermore, the prevalence of variants in the eight genes, including CDH1, was equal to or greater than that observed for CDH1 alone, suggesting that surveillance of carriers of pathogenic variants in these genes may be helpful for detecting gastric cancer, and these patients may benefit from a specific treatment, such as with a poly ADP-ribose polymerase inhibitor.
The study has some limitations, including that it is retrospective and that only single-nucleotide variants and small insertion deletions were analyzed, which may have underestimated the prevalence of germline pathogenic variants. However, the evaluation and eradication of H. pylori infection may be particularly important in individuals known to carry a pathogenic variant in a homologous recombination gene.