Beware of the horrific double-shot that raises the risk of gastric cancer by 45%

Working in tandem, a stomach microbe and rare variants found in nine genes greatly increase the lifetime risk of gastric cancer.

RIKEN researchers have found that genetics have a greater influence on the development of gastric cancer, the fourth most common cause of cancer death globally than previously thought.

In 2013, actress Angelina Jolie caused a stir when she announced that she had had a double mastectomy as a preventative measure against breast and ovarian cancer, which had led to the deaths of her mother, grandmother and aunt.

He based the decision on the discovery that it carried a rare variant of the BRCA1 gene that greatly increased her risk of developing breast cancer. The announcement generated widespread debate about the role genetics play in cancer, whether people should be screened, and what actions they should take in light of their genome.

This debate was thought not to be directly relevant to gastric cancer, as genetics were not known to play a major role in its development. Rather, its root cause was known to be a bacterium called Helicobacter pylori.

A cancerous infection

About half of the people in the world have it H. pylori in the stomach, having most often acquired the bacterium through contact with another person’s saliva, dental plaque, vomit or feces, but sometimes also through contaminated food or water.

Most people don’t know they have bacteria in their stomach because it usually doesn’t cause any symptoms. However, in the 1980s, two Australians, Barry Marshall and Robin Warren, discovered that the bacterium underlies the vast majority of stomach ulcers. Many scientists were initially dismissive of this claim as it flew in the face of the widespread wisdom that ulcers were primarily caused by stress and other lifestyle factors. However, further work vindicated Marshall and Warren, who shared a Nobel prize for the discovery in 2005.

Subsequently, H. pylori was linked to gastric cancer, earning it a classification among the highest class carcinogens, which include smoking, alcohol and excessive exposure to sunlight. The role of genetics was considered minimal, accounting for only 1% to 3% of cases.

A more nuanced perspective

Now, Yoshiaki Usui and Yukihide Momozawa of the RIKEN Center for Integrative Medical Science and their collaborators have shown that the reality of the situation is more nuanced. They found that having two risk factorsH. pylori infection plus carrying certain genetic variants greatly increases the likelihood of getting gastric cancer in your lifetime.

Specifically, they found that the lifetime probability of someone getting gastric cancer was less than 5%, regardless of their genetics, if they were H. pylori. This risk is increased to 14% for people infected with H. pylori, but who did not carry one of the rare high-risk genetic variants. But the real surprise was that for people who had both H. pylori and one of the variants found in four genes (which includes the variant that Angelina Jolie has), the risk has risen to more than 45%. These results have been published in The New England journal of medicine March 2023.

I suspected there might be an interaction between the genetic variants and… H. pylori on the risk of gastric cancer, says Usui. But the actual impact was much bigger than I had imagined.

Empower variant carriers

Importantly, this discovery offers hope to those who carry one of these genetic variants that they can be tested for. H. pylori and, if they are infected, they can take antibiotics to kill the bacterium, thus drastically reducing the risk of developing gastric cancer. Momozawa likes this aspect a lot.

As a geneticist, a lot of my work involves identifying genetic risk, and sometimes we can only provide a risk assessment for carriers, which isn’t very satisfying, she says. But this time we can provide genetic risk and effective treatment. This is a key point of this study.

The discovery also provides important insights into how gastric cancer develops. H. pylori it is known to damage[{” attribute=””>DNA by snapping its double strand in places. At the same time, four of the nine identified genes are involved in a process for fixing damaged DNA. If one of the high-risk variants of these four genes is present, the DNA-repair mechanism doesnt work and cells revert to another process for repairing DNA that is much more prone to introducing errors.
Thus, H. pylori damages DNA and the gene variants result in errors being introduced when this damage is repaired. This accounts for the high risk of getting gastric cancer when both factors are present.

This finding will also inform research on other cancers. Of the nine high-risk gastric cancer genes (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6 and PALB2) some, such as BRCA1 and BRCA2, have been linked to breast, ovarian, prostate and pancreatic cancer, while MLH1, MSH2 and MSH6 increase the risk of colorectal cancer.

Regional differences

To conduct the study, the team analyzed DNA samples from nearly 12,000 patients with gastric cancer and more than 44,000 people without cancer by drawing on two Japanese cohorts. But since H. pylori is more prevalent in East Asia and the strain in the region is particularly virulent, the results may be far less dramatic in other regions. Usui speculates that had the same study been conducted in USA or Europe, the differences in the gastric cancer risks might have been too small to pick up. This highlights the importance of doing genetic studies in different regions.

Commenting on the study, Nobel laureate Barry Marshall of the University of Western Australia says: 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 byYoshiaki 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