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Gastric Cancer Risk Variants, Pathogen Interactions Found in Retrospective Study

NEW YORK – A research team from Japan has cataloged genes and variants contributing to gastric cancer susceptibility, including genes that seem to interact with gastric cancer-related bacteria in the gut to mediate risk.

"Helicobacter pylori infection is a well-known risk factor for gastric cancer," senior and corresponding author Yukihide Momozawa, a researcher with the RIKEN Center for Integrative Medical Sciences, and his colleagues wrote in the New England Journal of Medicine on Thursday. "However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with H. pylori infection, on the risk of gastric cancer has not been widely evaluated."

With that in mind, the researchers relied on targeted sequencing to assess 27 cancer susceptibility genes in 10,426 gastric cancer cases and more than 38,100 cancer-free control individuals from Biobank Japan and in another set of 1,433 gastric cancer cases and nearly 6,000 controls enrolled through the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).

With the retrospective approach, the team tracked down gastric cancer-associated pathogenic variants in nine of the genes profiled. That collection included variants in homologous recombination-related genes that appeared to interact with the presence of H. pylori to influence gastric cancer risk, particularly in the HERPACC cohort.

"In addition to BRCA1 and BRCA2, seven genes (APC, ATM, CDH1, MLH1, MSH2, MSH6, and PALB2) had pathogenic variants associated with the risk of gastric cancer, and variant carriers had different clinical and demographic characteristics," the authors reported. "Furthermore, pathogenic variants and H. pylori infection interacted to markedly increase the risk of gastric cancer in persons with both risk factors."

In an email, Momozawa noted that CDH1 ties to gastric cancer susceptibility have been well established, while other genes in the collection were implicated in gastric cancer risk in some prior studies but were less firmly linked leading up to the latest large-scale analysis.

In contrast, he added, the interaction between H. pylori and germline risk variants had not been identified in the past, and points to the potential clinical benefits of testing for H. pylori in individuals carrying pathogenic homologous recombination gene variants and eradicating such infections if they do occur.

When they dug into the level of risk linked to H. pylori infection in individuals with or without germline risk variants in these genes, the researchers estimated that an 85-year-old carrying risky variants in combination with H. pylori bacteria would have a cumulative gastric cancer risk coming in at roughly 45.5 percent, while an H. pylori-infected individual of the same age would have a 14.4 percent cumulative risk of the disease in the absence of pathogenic germline variants.

"The effect that the interaction between germline pathogenic variants in homologous recombination genes and H. pylori infection had on gastric cancer risk was much larger than the effects of interactions between these variants and other environmental factors (smoking, drinking, obesity, and sodium intake)," the authors reported, adding that the interaction "was independent of the other environmental factors."

The team cautioned that the current analysis focused on SNPs and small insertions and deletions analyzed in specific cancer-related genes in East Asian participants in a retrospective manner, and suggested that further work is needed to explore potential contributions by copy number and other alterations in a more prospective or randomized manner.

"[A]lthough the patients with gastric cancer in this study are representative of the broader population of patients with gastric cancer encountered by clinicians in practice in East Asia, there are biologic differences between the East Asian and Western types of H. pylori," the authors wrote, noting that "[f]urther evaluations of the Western type of H. pylori are warranted."