A few weeks ago, I was drinking my coffee one morning while scrolling through my emails. They included my weekly table of contents from the New England Journal of Medicine which I was a bit annoyed at as they had once again rejected one of my papers that week. To be honest, I am getting a little tired of their repeated rejections and perhaps I will stop submitting to NEJM—they have never published any of my papers, as opposed to JAMA, Lancet, the Annals and The Jewish Link, some of the other great publications that have published my work.
Anyway, this week they did happen to have an awesome study and, reading it, I remembered why I enjoy medicine and science. It was an outstanding illustration of the principle of gene-environment interactions in cancer etiology—that while either genes alone or environmental factors alone could cause a disease, when both were present, the risk to individuals was additive or multiplied.
Gastric cancer remains one of the most common cancers in the world, though it is not common in the U.S. The reason for its high incidence rate worldwide is because of its association with Helicobacter pylori, a bacterial infection that is present in more than half the world’s population, though it is not so common in the U.S. or Europe. In particular, its prevalence is very high in East Asia, with concomitantly high gastric cancer rates there.
The study I read in NEJM was conducted by scientists from the RIKEN Center for Integrative Medical Sciences in Yokohama, Japan, led by Keitaro Matsuo and Yukihide Momozawa. They utilized a study population that included subjects from the Aichi Cancer Center. These subjects comprised 1,433 gastric cancer cases and 5,997 controls, individuals without cancer. Of the cancer cases, 1,236 were found to be positive for H. pylori (86.3%), while 2,776 of the control patients were positive for H. pylori (46.3%). This is certainly what one would expect for a gastric cancer case-control study conducted in Japan.
Here is where it gets interesting. The investigators went on to analyze the samples for the presence of mutations in 27 known pathological cancer-predisposing genes. Historically there has been one particular gene that has been associated with an increased risk for the development of gastric cancer, the CDH1 gene. But in this study, they found nine gene mutations to be associated with gastric cancer risk—CDH1, APC, ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6 and PALB2. These are all genes whose mutations are known to confer an increased risk of various cancers.
In the title of this article, I referred to gene-environment interactions. We generally believe that for most cancers, etiology is a consequence of changes in the genetic content of the cell somehow combining with some external lifestyle or environmental exposure. On some occasions, these interactions can be synergistic, i.e., the combination of the two can lead to a higher risk than either of the two acting separately—this higher risk can be additive or multiplicative. For those who were not carriers of these pathogenic genes and were uninfected by H. pylori, the cumulative risk of gastric cancer by age 85 appeared to be about 4%, while the cumulative risk for uninfected carriers was just under 5%. Those who were infected non-carriers appeared to have a risk of gastric cancer by age 85 of approximately 14.4%. However, those who were both H. pylori carriers and gene carriers had a risk of 45.5%. Wow!
While other infectious agents are associated with cancer causation, H. pylori is the only bacterium that is associated in that way. The prevalence of H. pylori in the U.S. is race/ethnicity specific. It is 60% among Hispanic people, about 50% among Black people, and only 20% among whites. Because it is a bacterium (the only bacterium implicated in cancer etiology), it has the advantage that it can be eradicated with antibiotics. This is a common intervention when H. pylori is detected by a gastroenterologist during an endoscopic examination of the stomach. And studies show that the eradication of H. pylori with antibiotics can rapidly reduce the risk of gastric cancer.
Gene-environment interactions are a common part of the fabric and tapestry of causation for various cancers. It can be taken advantage of for planning cancer-prevention programs. Other important gene-environment interactions include smoking and asbestos.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
