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By Eleanor McDermid, medwireNews Reporter

medwireNews: The presence of Helicobacter pylori alongside pathogenic variants in cancer-predisposing genes combine to increase the risk for gastric cancer, report researchers in The New England Journal of Medicine.

Yukihide Momozawa (RIKEN Center for Integrative Medical Sciences, Yokohama, Japan) and colleagues looked at the association between pathogenic variants in 27 risk genes and gastric cancer in 10,426 patients with gastric cancer and 38,153 controls from a Japanese cohort study.

They found significant associations for nine of these genes – APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2 – with odds ratios associated with pathogenic variants ranging from 3.48 for MSH6 to 14.45 for MLH1.

The team also collated information from a second hospital-based research program of 1433 patients with gastric cancer and 5997 without. The majority of gastric cancer patients – 88.9% of pathogenic variant carriers and 86.4% of noncarriers – had evidence of H. pylori infection. There was an interaction between infection and cancer risk genes such that risk increase for gastric cancer associated with pathogenic variants was 14.22-fold greater in people who were H. pylori-positive versus those who were negative.

Momozawa and team further found that this interaction was limited to the homologous-recombination genes, namely ATM, BRCA1, BRCA2 and PALB2, which they looked at separately “[b]ecause gastric carcinogenesis is related to genome instability caused by H. pylori infection”.

The cumulative risk for gastric cancer by the age of 85 years was less than 5% in people without H. pylori infection regardless of their carrier status but rose to 14.4% in infected people who lacked pathogenic variants in homologous-recombination genes and increased further to 45.5% in infected carriers.

In a linked editorial, Anne Müller and Jiazhuo He, both from the University of Zurich in Switzerland, say: “It is remarkable that pathogenic variants in homologous-recombination genes drive tumorigenesis only in the context of H. pylori infection.”

They call this “an example of ‘multihit’ carcinogenesis, in that two or more ‘hits’ are required for cancer to occur.”

The study findings have “numerous implications,” say the editorialists, “not only for the diagnosis, prevention, and possibly treatment of the fraction of cases of gastric cancer with pathogenic gene variants that arise due to H. pylori infection but also for a better understanding of the biology of other cancers arising on a background of homologous-recombination deficiency.”

They conclude: “It is quite conceivable that other DNA-damaging environmental factors contributing to human carcinogenesis have been overlooked.”

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

N Engl J Med 2023; 388: 1181–1190
N Engl J Med 2023; 388: 1225–1229