H. pylori infection has been etiologically linked to gastric cancer. Researchers have reviewed fundamental questions related to the ability of H. pylori to survive on the gastric surface, the role of virulence factors in gastric carcinogenesis, H. pylori-induced inflammation and genetic instability in the gastric mucosa, the history of H. pylori-related disease, and whether H. pylori eradication significantly reduces the incidence of gastric cancer. A related article was published in the journal Gastroenterology and was compiled by Medical Pulse as follows: However, it remains unclear how to reliably treat these infections or whether there is a population for which H. pylori may provide benefit. There are animal models of H. pylori-induced cancer, but unless the bacteria are combined with chemical carcinogens, none of these animal models can reliably produce malignancies similar to those found in humans. More importantly, treatment of infection in animal models usually leads to alterations in malignancy resolution or developmental abnormalities, calling into question their relevance to human gastric cancer. H. pylori as a major cause of gastric cancer H. pylori infection is necessary but not sufficient in the development of H. pylori-associated gastric cancer and is conceptually similar to hepatitis B and C viruses and human papillomavirus. Infection is necessary for gastric carcinogenesis, but H. pylori infection alone is not sufficient for gastric cancer formation and includes other factors. However, H. pylori is not the only cause of gastric cancer; other rare causes account for 3-5% of gastric cancers and include EBV infection, host genetic abnormalities, autoimmune gastritis, and proximal tumors that may be associated with esophageal adenocarcinoma. Thus, even in the absence of H. pylori, gastric adenocarcinoma is pretty much the same, rather than all gone. Gastric cancer is the leading cause of cancer deaths worldwide. The burden of gastric cancer is particularly high in Japan, so in February 2013 the Japanese government adopted insurance coverage for a gastric cancer prevention program that includes H. pylori screening and treatment (primary prevention) and post-treatment surveillance (secondary prevention for people with atrophic gastritis). In November 2014 the World Health Organization published the IARC Task Force Report, “Eradication of Helicobacter pylori as a strategy for gastric cancer prevention. This report is from a meeting held in December 2013. In addition, the recommendations of the Kyoto Global Consensus Conference on H. pylori Gastritis (held in January 2014) were published in early 2015. These recommendations state that “H. pylori gastritis should be defined as an infectious disease even if the patient is asymptomatic, regardless of complications such as peptic ulcer and gastric cancer …… Individuals with H. pylori infection should be given eradication therapy, unless conflicting considerations exist. “And” eradication of H. pylori reduces the risk of gastric cancer. The degree of risk reduction depends on the presence, degree, and extent of atrophic damage at the time of eradication.” In short, it looks like the trend has shifted to eradicating H. pylori, and the question of whether it will eliminate gastric cancer becomes moot – just as the question of whether eradicating poliovirus infection will eradicate polio. The question now is how to eradicate H. pylori in the most effective, cost-effective way. For example, should all populations in Japan be treated for infection? Should high-risk and high-prevalence populations in low-incidence gastric cancer areas such as the United States be treated? The magnitude of the problem has been elucidated separately for Japan and Korea, each of which has a high incidence of gastric cancer with nearly 80 million H. pylori-infected individuals. Although it is possible to eradicate H. pylori in Japan and Korea, in other countries with many infected patients, such as India, eradication is not possible because of its cost, the presence of other important infectious diseases, and the huge number of people who need treatment. In addition, in India and other developing countries, the rate of reinfection is high because of their poor sanitation and low standard of living. Vaccination is possible, but for prevention or advances in prevention and treatment, vaccines are disappointing, and funding for vaccine research is scarce. To date, in the 21st century, our understanding of the pathogenesis of H. pylori-associated disease and mucosal immunity has improved tremendously, and many of the problems that plagued H. pylori vaccine development are no longer insurmountable. H. pylori-associated gastric cancer Atrophic gastritis, a precursor to gastric cancer, can lead to little or no gastric acid production and can alter the microbiota of the stomach. The outcome of each infected individual is unpredictable, as is the degree of progression of gastric mucosal damage. However, further progression is halted by eradication. Eradication of H. pylori prior to atrophic changes essentially eliminates the risk of cancer. Depending on the degree and extent of atrophic changes, eradication can stop or possibly partially reverse the atrophic changes that occur, thus reducing the associated cancer risk. Similarly, there is a point in disease progression where a significant risk of cancer development remains despite H. pylori eradication. It is at this point that secondary prevention (e.g., endoscopic surveillance) programs may become cost effective in reducing gastric cancer deaths. Serum pepsinogen levels can be used to determine gastric cancer risk based on their ability to identify candidates suitable for a noninvasive, secondary prevention surveillance program (Figure 1). This approach precludes the need for endoscopy in most subjects; the use of validated tissue staging systems, such as the Validated Link for Gastritis Assessment (Figure 1), can specifically identify patients at potential risk. Importantly, tests measuring serum pepsinogen levels do not accurately identify patients with gastritis if they are treated with proton pump inhibitors or after H. pylori eradication. Figure 1 Screening and follow-up methods The ability to eradicate H. pylori to prevent gastric cancer formation depends on the patient’s level of cancer risk at the time of H. pylori eradication. Patients with non-atrophic gastritis can expect complete or near-complete protection. Patients with irreversible changes in the gastric mucosa are at high risk, but they can be assured that their risk is no longer increased and is likely to be reduced. Risk stratification can also identify patients who may benefit from a secondary cancer prevention program after H. pylori eradication. The benefits of H. pylori eradication also apply to patients at high risk of cancer death, such as those with early gastric cancer (gastric cancer confined to the gastric mucosa and submucosa, with or without local lymph node metastasis). In patients with successful endoscopic removal of early gastric tumors but who still have H. pylori infection, the risk of isochronous gastric cancer ranges from 1% to more than 4% per year. H. pylori eradication reduced their risk approximately 3-fold. The evidence that H. pylori eradication reduces the risk of gastric cancer raises questions about what H. pylori eradication accomplishes and how best to use this knowledge. H. pylori contributes to gastric cancer formation through persistent acute and chronic inflammation and altered genes and genetic phenotypes, leading to genetic instability in gastric epithelial cells. During tumor progression, gastric cancer cells acquire the ability to evade immune destruction, suppress the immune response, and begin to invade surrounding tissues. The interaction of H. pylori and other members of the gastric microbiota, endogenous and exogenous factors can also produce gastric carcinogens. Environmental factors, especially diet, are important population risk determinants (e.g., different diets or food preservation practices can influence the severity of gastric mucosal damage and cancer risk caused by H. pylori). Inflammation caused by H. pylori can lead to rapid renewal of gastric endothelial cells, producing a microenvironment rich in reactive oxygen and reactive nitrogen species, increasing the chance of DNA damage and somatic mutations (Figure 2). H. pylori can lead to methylation of multiple CpG islands, especially at sites encoding tumor suppressors such as calmodulin. H. pylori can also stimulate the activation of inducible cytidine deaminases, which can alter nucleotides. In addition, H. pylori infection can cause DNA double-strand breaks, altering the expression of microRNAs and increasing genetic instability. Many, if not most, of these H. pylori-related events (e.g., hypermethylation) are reversed after H. pylori eradication (Figure 3). Any improvement after H. pylori eradication will also reduce the overgrowth of non-H. pylori bacteria, potentially reducing or eliminating their deleterious effects. Table 2 Associated interactions between inflammation, bacteria and epithelial cells leading to gastric cancer Table 3 Genetic instability of epithelial cells due to H. pylori infection The risk of gastric cancer increases with increased infection with more virulent H. pylori strains, such as CagA-positive strains. Attempts to correlate specific H. pylori-associated diseases with individual putative virulence factors would yield discontinuous results, probably because most virulence factors are usually found with more virulent strains. There are no recognized virulence factors associated with specific diseases. However, they are usually associated with an increased inflammatory response and may be best understood as markers of inflammatory severity. Importantly, all H. pylori strains cause inflammation and disease of the stomach; no non-virulent strains were found. The difference in gastric cancer risk between the most and least virulent strains may be less than 3-fold, contributing to the recommendation that all H. pylori infections can be eradicated, regardless of virulence factors. Clinical findings Eradication of H. pylori reduced harmful irritation and contributed to the regression of inflammation. However, inflammation regression is a highly coordinated process regulated by anti-inflammatory molecules, including lipid mediators such as lipoxins and abscisins. This raises the question of if and/or when inflammation caused by H. pylori can subside. Gastric carcinogenesis is associated with inflammation. To increase our ability to discern whether inflammation subsides (or not), we should improve our insight into the influences that determine cancer risk after H. pylori eradication to help develop strategies to further reduce cancer risk. The high incidence of heterochronic cancer in patients who have undergone early gastric tumor resection may provide a high-risk group for clinical studies that can be conducted at a reasonable time with a reasonable sample size. For example, this population may be ideal for studies of risk factors for heterochronic cancer or randomized controlled trials of gastric cancer prevention (e.g., with antioxidants, cyclooxygenase II inhibitors, etc.). These individuals may also be studied for biomarkers used to confirm disease recurrence and progression. There is evidence that it is possible to reverse atrophic gastritis or gastric mucosal atrophy. For example, studies conducted prior to the discovery of H. pylori found that treating patients with atrophic gastritis or mucosal atrophy (autoimmune and H. pylori-related disease) with glucocorticoids resulted in partial recovery of the mural and principal cells. These findings have not been confirmed after patients begin treatment for H. pylori eradication. It may be unethical to use high doses of cortisol therapy to attempt to reverse atrophic changes, but it is possible to study atrophic gastritis while patients are receiving cortisol therapy for other conditions. Studies of patients and animals treated with tamoxifen have shown recovery of intestinal epithelial chemosis. Partial reversal of intestinal epithelial hyperplasia has also been found in animal models given adenosine diphosphate ribosylation inhibitors such as olaparib or prostaglandin E2. However, prostaglandin E2 is associated with the development of colon cancer and therefore should probably not be used in patients. In addition, these interesting findings suggest the possibility of at least partial reversal of atrophic gastritis. Evidence for a direct role of intestinal epithelial chemotaxis or antispasmodic peptide expression chemotaxis during gastric carcinogenesis is context-dependent; it is possible that reversal of atrophy may lead to detectable changes (e.g., related to differentiated transformation) without substantially altering cancer risk. Trials designed to reverse atrophic alterations must therefore also assess alterations in cancer risk, for example by reducing genetic instability in the involved mucosa. Finally, whole-genome sequencing analysis of gastric cancer has been initiated to identify factors that contribute to its formation. This information has been used to develop hierarchical molecular classification systems associated with genetic alterations of different etiologies of gastric cancer (e.g., H. pylori or EBV). These types of studies can lead to a better understanding of cancer treatment and pathogenesis.