Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer

Author(s): Yoshiaki Usui, M.D., Ph.D., Yukari Taniyama, Ph.D., Mikiko Endo, B.Sc., Yuriko N. Koyanagi, M.D., Ph.D., Yumiko Kasugai, M.M.Sc., Isao Oze, M.D., Ph.D., Hidemi Ito, M.D., Ph.D., M.P.H., Issei Imoto, M.D., Ph.D., Tsutomu Tanaka, M.D., Ph.D., Masahiro Tajika, M.D., Ph.D., Yasumasa Niwa, M.D., Ph.D., Yusuke Iwasaki, M.E., Tomomi Aoi, B.Sc., Nozomi Hakozaki, Sadaaki Takata, B.Sc., Kunihiko Suzuki, Chikashi Terao, M.D., Ph.D., Masanori Hatakeyama, M.D., Ph.D., Makoto Hirata, M.D., Ph.D., Kokichi Sugano, M.D., Ph.D., Teruhiko Yoshida, M.D., Ph.D., Yoichiro Kamatani, M.D., Ph.D., Hidewaki Nakagawa, M.D., Ph.D., Koichi Matsuda, M.D., Ph.D., Yoshinori Murakami, M.D., Ph.D., Amanda B. Spurdle, Ph.D., Keitaro Matsuo, M.D., Ph.D., and Yukihide Momozawa, D.V.M., Ph.D.
Source: N Engl J Med 2023; 388:1181-1190 DOI: 10.1056/NEJMoa2211807
Original Article
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Dr. Anjan Patel's Thoughts

Interesting correlation between H. Pylori infection and increased risk of gastric cancer in patients with pathogenic homologous-recombination mutations. The risk was additive and not multiplicative as many had thought.

BACKGROUND

Helicobacter pylori infection is a well-known risk factor for gastric cancer. 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.

METHODS

We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).

RESULTS

Germline pathogenic variants in nine genes (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2) were associated with the risk of gastric cancer. We found an interaction between H. pylori infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval [CI], 2.22 to 29.81; P=0.02). At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to 16.6]).

CONCLUSIONS

H. pylori infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.)

Author Affiliations

From the Laboratories for Genotyping Development (Y.U., M.E., Y.I., T.A., N.H., S.T., K. Suzuki, Y. Momozawa), Statistical and Translational Genetics (C.T.), and Cancer Genomics (H.N.), RIKEN Center for Integrative Medical Sciences, Yokohama, the Divisions of Cancer Information and Control (Y.U., Y.T., Y.N.K., H.I.) and Cancer Epidemiology and Prevention (Y. Kasugai, I.O., K. Matsuo), Department of Preventive Medicine, Aichi Cancer Center, the Divisions of Cancer Epidemiology (Y. Kasugai, K. Matsuo) and Descriptive Cancer Epidemiology (H.I.), Nagoya University Graduate School of Medicine, Aichi Cancer Center Research Institute (I.I.), and the Department of Endoscopy (T.T., M.T.), Aichi Cancer Center Hospital (Y.N.), Nagoya, the Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Medical School, Okayama (Y.U.), the Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation (M. Hatakeyama), the Department of Genetic Medicine and Services, National Cancer Center Hospital (M. Hirata, K. Sugano, T.Y.), the Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science (M. Hirata, Y. Murakami), and the Laboratories of Complex Trait Genomics (Y. Kamatani) and Clinical Genome Sequencing (K. Matsuda), Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, and the Department of Genetic Medicine, Kyoundo Hospital, Sasaki Foundation (K. Sugano), Tokyo, and the Research Center of Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo (M. Hatakeyama) — all in Japan; and the Population Health Program, QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute, Brisbane, Australia (A.B.S.).

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