Helicobacter pylori, inflammation-related genes, and gastric cancer

Inflammation induced by Helicobacter pylori is an important step in gastric carcinogenesis. Therefore studying the association between H. pylori, host genetic variations that predispose individuals to stronger inflammatory reaction, and risk of gastric cancer may shed some light on the etiology of this disease.; H. pylori is an important risk factor for gastric adenocarcinoma, but this association may vary by anatomic subsite (non-cardia vs. cardia), histologic subtype (intestinal vs. diffuse), and H. pylori strain (CagA positive vs. CagA negative). The first study in this dissertation, which is the largest prospective study of the association between H. pylori and gastric cancer conducted thus far, examined the H. pylori-gastric cancer association stratified by anatomic subsite and histologic subtype of the tumors and also by H. pylori strain. Seropositivity to H. pylori, defined as positive antibodies to either whole-cell antigen or CagA antigen, was associated with a 6--8 fold increased risk of gastric noncardia cancer but with a 50--70% reduced risk of gastric cardia cancer. This association did not differ by histologic subtype (intestinal vs. diffuse). Presence of antibodies to H. pylori CagA antigen did not change risk in subjects who were positive for H. pylori whole-cell antibodies but increased risk in subjects who were negative for these antibodies.; The second study examined the association between 17 single nucleotide polymorphisms in 8 inflammation-related genes and gastric cancer risk. We found no association between any of these polymorphisms and risk of gastric cancer. The results remained unchanged when analyses were stratified by anatomic subsite or histologic subtype of the tumors, or when results were adjusted for seropositivity to H. pylori.; Although H. pylori is an important risk factor for gastric non-cardia cancer, it may protect against risk of cardia cancer. Our findings are consistent with the hypothesis that a reduction in prevalence of H. pylori may have caused sharp declines in incidence of noncardia cancer but increased incidence of cardia cancer. Should these results be confirmed in future studies, we may need to identify carcinogenic and non-carcinogenic types of H. pylori and target treatment or eradication policies only toward the former types. CagA measurement was important in the current studies for correct diagnosis of previous long-term H. pylori infection, but it did not distinguish between carcinogenic and noncarcinogenic H. pylori, so further research in this area is required.