“Combination of Stomach Microbe and Gene Variants Raises Gastric Cancer Risk by 45%”

Researchers from RIKEN have uncovered a startling connection between the risk of gastric cancer and the presence of a specific stomach microbe called H. pylori, along with rare genetic variants in nine genes. This discovery highlights the potential for targeted antibiotic treatments to reduce the risk for individuals who are genetically susceptible.

When working in conjunction, the presence of H. pylori and specific gene variants significantly heightens the lifetime risk of developing gastric cancer.

Contrary to previous beliefs, RIKEN researchers have determined that genetics plays a more significant role in gastric cancer, which ranks as the fourth leading cause of cancer-related deaths worldwide.

In 2013, actress Angelina Jolie brought attention to the role of genetics in cancer when she underwent a preventive double mastectomy due to her high risk of breast and ovarian cancer. Her decision was based on the discovery of a rare variant in the BRCA1 gene, which substantially increased her susceptibility to breast cancer. This announcement sparked debates on genetic factors in cancer, the necessity of screening, and appropriate actions based on an individual’s genome.

Previously, this debate did not encompass gastric cancer since genetics were not thought to play a substantial role in its development. Instead, the primary cause was attributed to the presence of a bacterium known as Helicobacter pylori.

A Cancer-Causing Infection

H. pylori is found in approximately half of the world’s population, usually acquired through contact with saliva, tooth plaque, vomit, stool, or occasionally contaminated food and water.

Most individuals are unaware of the bacterium’s presence as it typically does not cause symptoms. However, in the 1980s, Australian scientists Barry Marshall and Robin Warren discovered that H. pylori was responsible for the majority of stomach ulcers. Initially met with skepticism, their findings contradicted the prevailing belief that ulcers resulted mainly from stress and lifestyle factors. Subsequent research confirmed their conclusions, leading to a Nobel Prize in 2005.

While it was known that H. pylori contributed to gastric cancer, genetics were considered a minor factor, accounting for only 1% to 3% of cases.

A Nuanced Perspective

Now, a team led by Yoshiaki Usui and Yukihide Momozawa from RIKEN Center for Integrative Medical Science has revealed a more nuanced understanding of gastric cancer risk. They discovered that individuals with both H. pylori infection and specific gene variants faced a significantly higher probability of developing gastric cancer over their lifetime.

The researchers found that individuals without H. pylori had a lifetime gastric cancer risk of less than 5%, regardless of their genetics. This risk increased to 14% for those infected with H. pylori but lacking the rare high-risk gene variants. However, the real surprise came when people had both H. pylori infection and one of the variants present in four genes (including the variant carried by Angelina Jolie). In such cases, the risk escalated to over 45%. These findings were published in The New England Journal of Medicine in March 2023.

Usui remarked, “I suspected there might be an interaction between the gene variants and H. pylori on gastric cancer risk, but the actual impact was much larger than I had imagined.”

Empowering Variant Carriers

Importantly, this discovery provides hope for individuals carrying these gene variants. They can undergo testing for H. pylori infection, and if positive, receive antibiotic treatment to eliminate the bacterium, significantly reducing their gastric cancer risk. Momozawa finds this aspect particularly promising, as it offers not only genetic risk assessment but also an effective treatment option.

Additionally, these findings shed light on the mechanisms of gastric cancer development. H. pylori is known to damage DNA by breaking the double strand, while four of the identified genes are involved in DNA repair processes. If a high-risk variant from these four genes is present, the DNA repair mechanism malfunctions, leading cells to adopt a less accurate DNA repair process that introduces more errors. Consequently, the combination of H. pylori-induced DNA damage and the presence of gene variants explains the elevated risk of gastric cancer.

Moreover, this research will inform studies on other cancers. Several of the nine high-risk gastric cancer genes identified (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2) are also associated with breast, ovarian, prostate, pancreatic, and colorectal cancers.

Regional Variations

To conduct their study, the team analyzed DNA samples from nearly 12,000 gastric cancer patients and over 44,000 cancer-free individuals using two Japanese cohorts. However, since H. pylori is more prevalent and virulent in East Asia, the results may have less impact in other regions. Usui speculates that conducting a similar study in the United States or Europe might yield smaller differences in gastric cancer risks, underscoring the importance of conducting genetic research across diverse regions.

Commenting on the study, Nobel laureate Barry Marshall from the University of Western Australia affirms, “This landmark study by Momozawa et al. has convinced me that H. pylori is the detonator for all kinds of carcinogenic agents, either environmental or genomic. In brief, H. pylori makes everything worse. Much worse.”

Reference: “Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer” by 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., 30 March 2023, The New England Journal of Medicine.
DOI: 10.1056/NEJMoa2211807

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More about gastric cancer risk

• RIKEN Center for Integrative Medical Science: Official Website
• The New England Journal of Medicine: Publication
• Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer: Research Article
• Barry Marshall, Nobel Laureate: University Profile
• Angelina Jolie’s BRCA1 Variant and Cancer Risk: News Article
• Role of Genetics in Cancer: American Cancer Society