TO THE EDITOR:
In “Clinical risk management of breast, ovarian, pancreatic, and prostatic cancers for BRCA1/2 variant carriers”, Ueki et al. nicely reviewed recommendations for measures to diagnosis earlier cancers associated with BRCA1/2 pathogenic germline variants (PGVs). They noted that BRCA carriers “might” also be at risk for stomach cancer [1]. Although there is not substantial evidence suggesting that BRCA1/2 PGV carriers should be routinely screened for stomach cancer, there is emerging evidence that those with BRCA 1/2 PGVs who are infected and not treated for H. pylori are at a substantially increased risk for stomach cancer.
In a recent New England Journal of Medicine article, Usui et al. demonstrated that persons with an H. pylori infection and homologous-recombination pathogenic germline variants (PGVs)-including BRCA PGVs-have a cumulative lifetime risk of 45.5% for developing gastric cancer [2]. For those with CDH1 PGVs, the lifetime gastric cancer risk is roughly 38%, and prophylactic gastrectomy or screening for gastric cancer is recommended [3, 4]. Therefore, it might seem reasonable to consider screening all BRCA1/2 carriers for H. pylori and, if detected, it would seem worthwhile to also screen those patients for gastric cancer and aggressively treat H. pylori in those not found to have gastric cancer.
Based on a comprehensive review of H. pylori incidence and its relationship to the development of gastric cancer, the International Agency for Research on Cancer recommends “tailored” surveillance and eradication of H. pylori [2, 5]. A randomized, controlled trial showed that eradication of H. pylori reduced gastric cancer incidence [6]. Such an approach to screening, treatment and surveillance of H. pylori would be particularly reasonable for BRCA 1/2 carriers. Usui et al. showed that both BRCA1 and BRCA 2 carriers had similar age of gastric cancer diagnosis (roughly age 64) and similar Odds Ratios for developing gastric cancer (4.81 and 5.08, respectively) [2]. Usui et al. also noted that the average age of gastric cancer diagnosis was “more than 10 years younger” among PGV carriers compared to non-PGV carriers [2].
Genes are typically classified as PGVs related to their penetrance for developing a particular cancer without respect to environmental influences. The thorough review of Ueki et al. illustrates why defining BRCA1/2 penetrance for developing gastric cancer independent of environmental influences excludes patients from recommendations that might profoundly help them in part because Usui et al. demonstrated that BRCA1/2 and other homologous-recombination PGVs in the context of H. pylori infection as are gastric cancer predisposing. If BRCA1/2 PGVs are reclassified as gastric cancer predisposing in the setting of H. pylori infection, management recommendations-such as those described by Ueki et al.-will include more testing for, treatment of, and eradication of H. pylori in this group and their high risk for developing gastric cancer will hopefully be mitigated.
References
Ueki A, Yoshida R, Kosaka T, Matsubayashi H Clinical risk management of breast, ovarian, pancreatic, and prostatic cancers for BRCA1/2 variant carriers. J Hum Genet. 2023. https://doi.org/10.1038/s10038-023-01153-1. Online ahead of print.
Usui Y, Taniyama Y, Endo M, Koyanagi YN, Kasugai Y, Oze I, et al. Helicobacter pylori, homologous-recombination genes, and gastric cancer. N Engl J Med; 388: 1181-90.
Robert ME, Ranola JMD, Marshall ML, Susswein LR, Graceffo S, Bohnert K, et al. Comparison of CDH1 penetrance estimates in clinically ascertained families vs families ascertained for multiple gastric cancers. JAMA Oncol. 2019;5:1325–31.
Ajani JA, D’Amico TA, Bentrum DJ, Cooke D, Corvera C, Das P, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Gastric Cancer. Version 1.2023-March 10, 2023.
Helicobacter pylori eradication as a strategy for preventing gastric cancer. Vol. 8. IARC Working Group Report. Lyon, France: International Agency for Research on Cancer, 2014 (https://publications.iarc.fr/Book-And-Report-Series/Iarc-Working-Group-Report/-Em-Helicobacter-Pylori-Em-Eradication-As-A-Strategy-For-Preventing-Gastrc-Cancer-2014).
Choi IJ, Kim CG, Lee JY, Kim YI, Kook MC, Park B, et al. Family history of gastric cancer and Heliobacter pylori treatment. N. Engl J Med. 2020;382:427–36.
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Dr. Sorscher was formerly and briefly employed by Invitae, Corp.
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Sorscher, S. Helicobacter pylori and gastric cancer risk in BRCA 1/2 pathogenic germline variant carriers. J Hum Genet 68, 725 (2023). https://doi.org/10.1038/s10038-023-01177-7
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DOI: https://doi.org/10.1038/s10038-023-01177-7
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