Adenocarcinoma of the stomach is one second most common cause of cancer mortality in the world, and epidemiologic studies have indicated that early-life exposure to an environmental agent is associated with later cancer risk. Once acquired, Helicobacter pylori causes chronic superficial gastritis, and is the major cause for this process throughout the world. Previous work indicates that chronic superficial gastritis may progress to atrophic gastritis, which in some cases leads to cancer. A wide variety of data indicate the biological plausibility of persistent H. pylori infection playing a role in pathogenesis of gastric cancer, and several epidemiologic studies have demonstrated a direct association. A growing body of evidence suggests that intensity of inflammation and heightened humoral response to H. pylori enhance cancer risk. However, most H. pylori-infected persons do not develop gastric cancer. The purpose of the proposed study is to identify further H. pylori-linked markers for persons at high or low risk of developing gastric cancer. Serum and gastric tissue specimens have been acquired from three previous studies (Minnesota, Hawaii, Japan) in which an association of H. pylori infection and gastric cancer have been shown, and from villagers in Shandong Province in China who differ substantially in cancer risk. Using these specimens, we will address three hypotheses concerning risk of developing gastric cancer. First, that strain-specific H. pylori characteristics affect risk. We will focus on alleles of vacA, the gene encoding the vacuolating cytotoxin, since previous data indicate that in vitro expression of toxin production is associated with enhanced inflammation. Second, that host responses to conserved H. pylori antigens represent markers for risk. We will explore the relationship of serum IgA and IgG responses to conserved antigens including the hspA and hspB products. Third, we will explore whether specific host tissue responses to H. pylori antigens are risk factors. Utilizing blocks of unaffected gastric tissue from cancer patients and controls, we will explore whether H. pylori- induced production of pro-inflammatory cytokines or growth factors is associated with disease outcome. From these studies, we hope to define markers for gastric cancer risk as well as to better understand intermediate mechanisms in its pathogenesis.
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