Research into Gastric Cancer
Background
Helicobacter pylori infection is causal for non-cardia gastric cancer. Independently, the Branch discovered that non-cardia gastric cancer risk was significantly increased with polymorphisms in pro-inflammatory variants in the IL-1 gene cluster. The risk was found to be additive with multiple variants and to include other genes related to innate immunity and Th1-type cell-mediated responses. The association was specific for non-cardia gastric cancer, excluding esophageal carcinomas as well as cardia gastric cancer. However, in FY2006 a meta-analysis led by the Branch found highly significant heterogeneity, in which pro-inflammatory gene variants were associated with gastric cancer risk only in some populations of European ancestry. They were not associated with gastric cancer risk in Asian populations. These results suggest strong interactions with environmental factors, perhaps including diet, variants of H. pylori, and co-infections. IIB has started and is planning novel approaches to clarify some of these complex factors.
H. pylori Th1/Th2 Responses
The risk of non-cardia gastric cancer is relatively low in Africa although H. pylori infection is highly prevalent, occurs at a young age and persists throughout life. Using residual serum samples from rural Tanzania, in FY2006 we started investigating the hypothesis that populations where gastric cancer incidence is low despite high H. pylori prevalence are characterized by Th2-dominant immune responses. We are determining Th1/Th2 using novel IgG1/IgG2 H. pylori-specific subclass antibodies. This analysis will be completed in FY2007. To further test the pro-inflammatory hypothesis, in FY2007-2008 we plan to obtain residual serum samples for Th1/Th2 responses (IgG1/IgG2 H. pylori-specific subclass antibodies) from subjects with and without esophageal and gastric dysplasia in rural Kenya, where gastric cancer and esophageal cancers are more common.
EBV-Associated Gastric Cancer
Five to 15% of non-cardia gastric cancers have detectable EBV gene products or genome. IIB will soon complete an analysis confirming that elevated titers of EBV anti-VCA are associated with gastric cancer risk. During FY2007, the Branch plans to begin organizing an international consortium of studies to accumulate perhaps 5000 previously diagnosed gastric cancer cases with epidemiological and laboratory data from both high (e.g., Japan, South America) and low (e.g., U.S.) incidence populations. In FY2008, gastric tissue for EBV testing would be obtained from 4 or 5 completed studies that have extant questionnaire and polymorphisms data on approximately 1500 cases. Data from this pilot would be summarized and used to recruit additional completed cohort and case-control studies to provide gastric tissue for EBV classification, as well as epidemiological data for collaborative re-analysis. If tissues are sufficient, microarrays would be constructed for independent analyses. EBV-positive cancer cases would be compared to disease-free controls as well as to EBV-negative cases in case-control and case-case analyses. The goal is to complete initial analyses of risk factors for EBV associated gastric cancer with specimens and data from the consortium in FY2009.
