Factors Contributing To Malignancy

With only 1% of people infected with H. pylori developing gastric adenocarcinoma, the vast majority of infected persons have no clinical symptoms. Any model that attempts to describe H. pylori as a risk factor for gastric cancer must explain why this disease develops in some people but not in others (144). Factors that could explain this variability include: differences in H. pylori genotype, host genotype, age at infection, and exposures to environmental cofactors (Fig. 3).

H. pylori Genotype

The genetic diversity between strains of H. pylori is wide. Identical H. pylori strains are rarely, if ever, seen in unrelated individuals (145) and within families, strains frequently differ (146). Even within an individual, variability of the infecting strain may exist (147). Little is known about the clinical significance of these strain differences. The prognostic value of combinations of alleles for different virulence factors is being explored (37-39). Strains containing the H. pylori pathogenicity island increase an individual's risk of intestinal-type gastric cancer when compared with strains that do not (71,72). Similarly, H. pylori-infected people with CagA antibodies are two times more likely to progress from nonatrophic gastritis to atrophic gastritis than are H. pylori-infected people without these antibodies (148).

Although the prevalence of strains with the pathogenicity island varies across populations (149,150), it is not clear that this variation translates into differences in disease incidence. Moreover, variation in H. pylori strain type cannot explain the differences between population rates of peptic ulcer disease and gastric cancer, as CagA-positive strains appear to increase risk for both of these conditions (151).

Human Genotype

A variety of human genetic factors have been associated with H. pylori carcinogenesis; any could predispose infected hosts to one disease outcome and prevent another. Glutathione-5-transferase-^ (GSTM1) conjugates and detoxifies carcinogenic compounds; specific genotypes may be associated with cancer risk (152-154) and, in combi-

Fig. 3. Model of progression of H. pylori-associated clinical conditions. H. pylori causes gastritis, either confined to the antrum or corpus-wide; this distribution is probably associated with age at infection and/or host susceptibility. Antrum-based infection causes increased acid production and increased risk of duodenal ulcer (DU). Corpus infection leads to decreased acid levels via loss of parietal cells through atrophy. In a subset of persons with chronic atrophic gastritis, this low acid environment predisposes to the development of gastric ulcer and/or cancer. Of note, DU patients on long-term anti-acid regimens could potentially develop CAG. Each step in this model could be affected by environmental factors (e.g., diet or smoking), H. pylori genotype (e.g., cagA), or host genotype.

Fig. 3. Model of progression of H. pylori-associated clinical conditions. H. pylori causes gastritis, either confined to the antrum or corpus-wide; this distribution is probably associated with age at infection and/or host susceptibility. Antrum-based infection causes increased acid production and increased risk of duodenal ulcer (DU). Corpus infection leads to decreased acid levels via loss of parietal cells through atrophy. In a subset of persons with chronic atrophic gastritis, this low acid environment predisposes to the development of gastric ulcer and/or cancer. Of note, DU patients on long-term anti-acid regimens could potentially develop CAG. Each step in this model could be affected by environmental factors (e.g., diet or smoking), H. pylori genotype (e.g., cagA), or host genotype.

nation with H. pylori, may amplify this risk. The acid response to H. pylori may have a genetic basis, as may the rate of proliferation of the gastric mucosa (155,156). Human leukocyte antigen (HLA) types show associations with atrophic gastritis, duodenal ulcer, and gastric cancer although associations with H. pylori remain unexamined (157-159). Additional human genetic factors that are being explored in relation to infection include ABO blood group type, Lewis blood group type, and mucin genotype (160-164).

Age at Infection

Similar to other cancers associated with an inflammatory process (165-167), the risk of gastric cancer may correlate with the length of time that a person has been infected with H. pylori. People infected with H. pylori as children have more time to acquire necessary mutations over their lifetime compared to those infected as adults. In developed countries, it appears that the average age of acquiring infection is increasing over time (41,42), possibly explaining in part the decline in cancer rates and the increase in age at which cancer occurs. It is difficult, however, to prove that the age of infection influences disease outcome. In mice, infection is more likely to persist if infection occurs at a young age, producing multifocal gastritis (168), suggesting a different susceptibility of the young stomach. The stomach of a human child may be physiologically different that that of an adult. Children have less acute inflammation and more prominent lymphoid follicles than do adults (169); they may also be more likely to have H. pylori in the corpus of the stomach (170). This would increase their likelihood of hypochlorhydria, explaining why, even with antral gastritis, duodenal ulceration is a rare response to childhood H. pylori infection (169).

It is possible that factors that cause hypochlorhydria in childhood, such as malnutrition and infectious diseases, are necessary for cancer formation. Under hypochlorhy-dric conditions, H. pylori could extend into the gastric corpus, initiating the chain of events that leads to malignancy. In the absence of malnutrition or infection, H. pylori would remain confined to the antrum and intraluminal acid levels would remain normal or high.

Environmental Cofactors for Infection

The effects of other known risk factors for gastric cancer could be modified by the concurrent presence of H. pylori. For example, it appears that diets high in salt and nitrates increase cancer risk while diets rich in fresh fruits and vegetables protect against gastric cancer (123). Because H. pylori both induces nitric oxide formation (potentially fostering the formation of A-nitroso compounds from intraluminal nitrites) and destroys mucosal ascorbate, the interaction of infection with diet may have an effect far greater than each alone in causing cancer. In the same way, cigarette smoking potentially alters the outcome of H. pylori infection (171,172), again via the nitric oxide pathway (173). Also of interest, some gastric adenocarcinomas have clonal integration of Epstein-Barr virus (174,175), although a relationship with H. pylori remains unclear.

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