Genetic variants increase risk for H. pylori-related stomach cancer
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Key takeaways:
- Genetic risk factors and H. pylori infection concomitantly increase risk for gastric cancer.
- Results showed “compelling evidence” that a wider array of genetic variations influence gastric cancer risk.
Individuals with certain germline pathogenic variants had a substantially higher risk for developing gastric cancer after Helicobacter pylori infection, results of a Japan-based case-control study showed.
The findings, published in The New England Journal of Medicine, suggest risk for gastric cancer is more heavily related to hereditary factors than previously thought, the investigators noted.
Four of the nine cancer-predisposing genes identified by the researchers are involved in the process of repairing damaged DNA, according to Yoshiaki Usui, MD, PhD, of RIKEN Center for Integrative Medical Sciences in Yokohama, Japan.
“H. pylori infection leads to cancer because it promotes DNA double-strand breaks and destabilizes the DNA of stomach cells,” Usui said in a press release. “Combining that with genetic variants that prevent normal damage repair appears to substantially enhance the risk for gastric cancer.”
Background
H. pylori is a WHO Group 1 carcinogen, and those of East Asian descent are known to be at highest risk for developing related gastric cancer, the investigators wrote.
Ongoing research continues to identify genetic variations of interest across a wider array of cancer types, according to Yukihide Momozawa, DVM, PhD, team leader in the Laboratory for Genotyping Development at RIKEN. The combined effect of H. pylori infection and these genetic variants on risk for developing subsequent gastric cancer remains unknown, he added.
“The impact of rare variants on cancer development has been of interest because it has the potential to predict risk and prevent the onset of the disease before it develops, as well as to expand the application of specialized drugs,” Momozawa told Healio.
Methodology
Usui and colleagues conducted a case-control study using two independent study cohorts to identify any association between germline pathogenic variants in 27 known cancer-predisposing genes and risk for gastric cancer. They then evaluated the combined effect of pathogenic variants and H. pylori infection status on gastric cancer risk.
The investigators conducted a genomic analysis of DNA from 10,426 patients with gastric cancer and 38,153 control subjects from BioBank Japan for the first analysis. Researchers used another cohort of 1,433 patients with gastric cancer and 5,997 control subjects from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) for the second risk analysis.
Key findings
The investigators observed an association between germline pathogenic variants in nine cancer-predisposing genes — APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6 and PALB2 — and increased risk for gastric cancer.
Researchers noted increased risk for gastric cancer when analyzing the interaction between H. pylori infection and pathogenic variants in homologous-recombination genes among patients included in the HERPACC study sample (excess RR = 16.01; 95% CI, 2.22-29.81).
Individuals aged 85 years without infection had a less than 5% cumulative risk for gastric cancer regardless of their gene variant status compared with 14.4% (95% CI, 12.2-16.6) among noncarriers of pathogenic variants in homologous-recombination genes infected with H. pylori and 45% (95% CI, 20.7-62.6) among carriers infected with H. pylori.
Clinical implications
The results showed genetic risk factors and H. pylori infection concomitantly increase the risk for gastric cancer, according to Momozawa.
“This suggests that carriers of the genetic risk could be rescued by the evaluation and eradication of H. pylori infection,” he told Healio.
Future studies should examine more cancer-predisposing genes for links to gastric cancer, Momozawa added, including further investigation of well-studied BRCA1 and BRCA2 genes, which have potential clinical utility for management of the disease.
The results show “compelling evidence” that a wider array of genetic variations have influence on increased risk for gastric cancer, especially genes involved in DNA repair, according to Anne Müller, PhD, and Jiazhuo He, MD, of the Institute of Molecular Cancer Research at University of Zurich.
“[The] findings imply that the hereditary contribution to the risk [for] gastric cancer is more important than previously believed and suggests that DNA damage induced by H. pylori, if repaired incorrectly or not at all, is a major driver of gastric carcinogenesis,” they wrote in an accompanying editorial.
“Germline pathogenic variants in ATM, BRCA2, BRCA1 and PALB2 are known to cause a predisposition to breast, ovarian, prostate and pancreatic cancer,” they added. “Gastric cancer, at least in the context of H. pylori infection, has now been added to this list.”
References:
- Müller A, et al. N Engl J. Med. 2023;doi:10.1056/NEJMe2215503.
- RIKEN Center for Integrative Medical Sciences. Pathogenic genetic variations boost the risk of H. pylori-related stomach cancer (press release). Published March 29, 2023. Accessed March 29, 2023.
- Usui Y, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2211807.
For more information:
Yukihide Momozawa, DVM, PhD, can be reached at Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan; email: momozawa@riken.jp.
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