Genetic Susceptibility to Infection Related Cancer

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DESCRIPTION (provided by applicant): The long-term goal of the proposed study is to provide a scientific basis to develop efficient primary prevention strategies against infection/inflammation-related cancers. Mounting evidence suggests that a variety of infectious agents have a role in the pathogenesis of human cancers. It is estimated that 15.6 percent of the worldwide cancer incidences in 1990 can be attributed to these infectious agents, accounting for a total of 1,450,000 cases. Helicobacter pylori (HP) is ranked top among various infectious agents and represents approximately 5 percent of new cancer cases in the world. These cancers are important from a public health point of view because they are potentially preventable by antibiotics treatment or vaccination. Whereas HP infection is very common (80-90 percent) in populations with high risk for stomach cancer, it is known that only a very small fraction of the population infected with HP actually develops cancer, suggesting a role for genetic components in HP-related carcinogenesis in addition to that of environmental co-factors. This proposal will specifically focus on the 2 groups of polymorphic genes, receptors to HP lipopolysaccharide (LPS), a cell wall component, which elicits immediate proinflammatory responses, (1) CD14 (C-260T), (2) TRL4 (A896G) and (3) NOD2 (3020insC); and resultant cytokines, (4) IL-8 (T-251A), (5) MCP1 (G-2518A), (6) IL-lbeta (T-31C) and (7) TNF-alpha (G-308A). These polymorphic genes are known to be functional and have been postulated to modify host responses to HP infection. The proposed study will be designed as a spin-off study of a chemo prevention trial for gastric cancer in Venezuela, taking advantage of unique characteristics of the study population, i.e., a strikingly high (95 percent) HP infection rate and high prevalence of gastric premalignant lesions. It will utilize biological specimens and epidemiological and histopathological data collected at the baseline examination from the 2200 participants. Genomic DNA will be isolated from these specimens and tested for the polymorphic genes listed above. The specific aim of the proposed study is to evaluate whether those genotypes or alleles of the polymorphic genes which lead to greater responses to HP infection are associated with increased risk of high-grade gastric precancerous lesions. Secondary aims include to examine histopathological correlates of these polymorphisms and to determine whether selected environmental factors modify the above associations.