We read Dr. Sorscher’s comments  with great interest and appreciated his valuable suggestions about our article . Based on the recent paper written by Usui et al. , he emphasized the increased risk of developing gastric cancer due to Helicobacter pylori (H. pylori) infection in carriers of the BRCA1/2 pathogenic germline variant (PGV), and recommended eradication of H. pylori if positive. Usui et al. conducted a hospital-based epidemiological study, using 1433 gastric cancer patients and 5997 controls, and demonstrated an approximately three-fold increasing risk of gastric cancer due to H. pylori infection in BRCA1/2 PGV carriers in Japan (a cumulative lifetime risk at 85 years of age: 45.5% vs. 14.4%) .
The prevalence of H. pylori infection is relatively high in East Asian countries (seroprevalences: 59.6% in Korea, 58.1% in China, 57% in Thailand, 54.5% in Taiwan, and 39.3% in Japan) , where there are similarly high incidences of gastric cancer. Cytokine-associated gene A (CagA) is the major virulence factor associated with gastric carcinogenesis. CagA is positive in almost all H. pylori strains; however, the level of virulence is higher in the East Asian-type CagA strain than in the Western-type CagA strain owing to structure variants . In H. pylori infection, CagA injected into gastric epithelial cells interacts with PAR1b and subverts the nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. Oxidative stress due to H. pylori infection also induces BRCAness, which promotes DNA double-strand breaks while disabling error-free homologous recombination (HR)-mediated DNA repair . These molecular mechanisms are thought to further reduce DNA damage-repair capacity in individuals with deleterious variants of HR-related genes .
According to a nationwide case-control study by Momozawa et al., the risk of esophageal cancer is also increasing in Japanese BRCA2 PGV carriers (odds ratio: 5.6 [95% confidence interval: 2.9–11.0]) . Interestingly, heterozygous BRCA2 truncation, which lowers BRCA2 expression, sensitizes to BRCA2 haploinsufficiency induced by transient exposure to formaldehyde or acetaldehyde . In this phenomenon, the need for genetic analysis of the ALDH2 (aldehyde dehydrogenase 2) gene is commonly emphasized, as this polymorphism is relatively common in the Asian population and is also associated with an increasing risk of esophageal cancer due to the carcinogenic accumulation by acetaldehyde. Endoscopic surveillance is recommended  along with the reduction of additional risks (e.g., drinking and smoking).
As mentioned above, and as shown in the comments by Dr. Sorscher, cancer risk generally consists of environmental, lifestyle, and genetic factors, in addition to aging. Modifiable risk factors should be reduced in individuals with inherited risks. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) recommends H. pylori eradication and surveillance using upper gastrointestinal endoscopy in Lynch syndrome patients, of whom the lifetime risk of gastric cancer is 6–13% . Accordingly, H. pylori eradication (when positive) and upper gastrointestinal surveillance in BRCA1/2 PGV carriers are warranted. This topic should be reconsidered when the guidelines for hereditary breast and ovarian cancer (HBOC) are revised in the near future.
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All four authors are members of the HBOC guideline committee at the time of manuscript submission.
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Matsubayashi, H., Kosaka, T., Yoshida, R. et al. A commentary on Helicobacter pylori and gastric cancer risk in BRCA1/2 pathogenic germline variant carrier. J Hum Genet 68, 727–728 (2023). https://doi.org/10.1038/s10038-023-01183-9