Gastric adenocarcinoma, the second cause of cancer-related deaths in Latin America, is associated with the high prevalence of infection with the type I carcinogen Helicobacter pylori. Several immunological events are associated with the inflammatory response in the stomach of infected individuals, which is associated with gastric carcinogenesis. This response is mediated by the Toll-like-receptors, pro-inflammatory cytokines such as interleukin-8 (IL8), 1L-1? and TNF-?, and the pro-inflammatory enzyme COX-2. Correa has proposed a progression model for the development of intestinal-type gastric adenocarcinoma, originally based on histopathology observations, but consistent with the effects of the pro-inflammatory immune response against H. pylori infection. However, there is substantial inter-individual variation in this progression, as well as in symptoms and clinical manifestations of carcinogenesis. Part of this variability is due to host genetic factors. The main goal of this proposal is to test the hypothesis that host genetic variants in TLR2, COX2, IL1B, ILRB, IL8 and IL8RA which are key components of the immune response against H. pylori infection, are associated with susceptibility to gastric adenocarcinoma in Peruvian and Brazilian admixed populations. We propose to perform a case-control association to with the following specific aims: (1) To collect clinical data and DMA samples of 860 gastric adenocarcinoma patients and 860 controls, 500 matched pairs from Lima (Peru) and 360 matched pairs from Rio de Janeiro (Brazil). (2) To quantify the levels of COX-2 and IL-8 in the stomach of gastric cancer patients and in a subset of controls by immunohistochemical analysis of biopsy specimens. (3) To identify the most informative set of tag-SNPs in TLR2, COX2, IL1B, ILRB, IL8, IL8RA and IL8RB to be used in genetic association studies in the selected populations and (4) To test the statistical association among haplotypes of TLR2, COX2, IL1B, ILRB, IL8 and IL8RA and: (a) levels of IL-8 and COX-2 in the stomach and (b) gastric adenocarcinoma, controlling for the effect of potential confounding variables such as admixture. We propose to develop a multi-centric study using a gene-candidate approach, capitalizing data demonstrating the role of the selected genes in the pathogenesis of gastric adenocarcinoma. By performing the study in Lima and Rio de Janeiro, we address the key issue of replication of genetic association studies. ? ? ?
