Gastric tumors and tissues from humans and mice accumulate somatic mutations in various genes in the gastric mucosa upon Helicobacter pylori infection, researchers report in the August issue of Gastroenterology.
In the study, Takahiro Shimizu et al. show that increased cytidine deaminase activity in these tissues promotes the accumulation of these mutations and might promote gastric cancer development in patients with H pylori infection.
We asked study co-author Hiroyuki Marusawa some questions about the study—here are his answers.
Q: You identified a specific mutational signature in H pylori-induced gastritis and gastric cancer. What gave you the idea to look for this pattern?
A: Recent cancer genome sequence analyses revealed that mutational signatures of cancer genomes can identify possible causes of mutagenesis. On the other hand, we previously found that a DNA mutator enzyme, activation-induced cytidine deaminase (AICDA or AID), is upregulated in response to H pylori infection. It induces somatic mutations in several target genes of gastric epithelial cells. We investigated whether human gastric mucosa with H pylori infection contains somatic mutations, with signatures specific for AID activity.
Q: The mutational signature is dominated by C>T transition in GpCpG trinucleotides. How do these mutations accumulate specifically in H pylori-infected gastric tissue (as opposed to non-infected tissue)?
A: Somatic mutations of C>T transition in GpCpG trinucleotides are the typical footprint of AID-mediated mutagenesis. AID expression is induced by H pylori infection in gastric epithelium, whereas no AID expression is observed in non-infected gastric mucosa. Together, these findings indicate that H pylori infection induces C>T transitions in GpCpG trinucleotides through the mutagenic activity of AID activity in patients with H pylori infection.
Q: You show that mice that overexpress AID develop specific C>T mutations in TP53 similar to those of human H pylori-associated gastric cancers. Could AID or its pathway be a therapeutic target?
A: Yes, we think that AID can be a nice therapeutic target for the prevention of gastric cancer development. But we have to pay attention to the fact that AID is an essential enzyme for generating the antibody diversity in B cells. Unfortunately, it is technically difficult to inhibit the AID activity specifically in gastritis mucosa.
Q: Gastric, esophageal, and colorectal adenocarcinomas also have high numbers of C>T transitions in CpG dinucleotides. However, H pylori is not a known contributor to colorectal or esophageal cancers—does this mean that AID is not the sole determinant of these alterations? What could be causing these transitions in these other GI tissues?
A: AID expression is induced not only by H pylori infection but also by several inflammatory cytokine stimulation in gastrointestinal epithelial cells. For example, tumor necrosis factor (TNF) can induce the upregulation of AID in colonic epithelial cells. Moreover, bile acid reflux promotes expression of AID in the esophageal mucosa. It is therefore possible that a subset of the C>T transition mutations detected in esophageal and colorectal cancers could be attributed to AID-mediated mutagenic activity.
Q: If mutations in TP53 and ARID1A can already be detected in non-tumor gastric tissues of patients with H pylori–induced gastric cancer, what additional events do you think are required for gastric tumor formation? Do you think that TP53 and ARID1A mutations are the first events in the pathway to gastric cancer, and then other events are required for malignant tumors to form?
A: Yes, we believe that TP53 and ARID1A mutations are essential events in the pathway to gastric cancer. Additional genetic and/or epigenetic alterations would be required for malignant transformation of gastric epithelial cells during the development of gastric cancers.
Q: New sequencing technologies are being rapidly developed. What kinds of questions about gastric cancer pathogenesis do you see us being able to answer in the future, using these new tools?
A: Using the deep-sequencing technology, we might be able to identify new mutations that promote gastric carcinogenesis. In addition, a vast amount of information about the mutation signature would provide us the opportunity to define the factors that induce genetic alterations during tumorigenesis.
Q: What are you going to study next?
A: We would like to understand the relationship between genetic and epigenetic alterations in H pylori-infected gastritis mucosa during the development of gastric cancers. This is because AID has a role on the regulation of demethylation under various physiologic and pathologic conditions.