H. pylori ancestral haplotype a gastric cancer risk determinant in Latin America

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DESCRIPTION (provided by applicant): Gastric cancer is the leading global cause of infection-related cancer mortality and overall is the second leading cause of cancer death. It is projected to rise to eighth in all-cause mortality in the near term. Gastric cancer has a marked geographic variability, with high incidence areas including Latin America and eastern Asia, which affords the opportunity for accelerated scientific investigation and focused intervention programs. Helicobacter pylori (Hp) is the dominant risk factor for gastric cancer. A host of strai specific genetic factors affect gastric cancer risk, such as the cagA and vacAs1m1 genotypes. However, it is clear that other bacterial constituents need to be identified to better understand oncogenic mechanisms and explain differences in individual and population risk, especially if biomarkers are to be developed. Recent investigations suggest that the H. pylori phylogeographic origins, as determined by ancestral haplotypes with Multilocus sequence typing (MLST), may help delineate H. pylori associated cancer risk, based upon studies of subjects with chronic gastritis from high and low incidence regions of Colombia. This proposal is the planned expansion of the PI's ongoing gastric cancer epidemiology initiative in Central America (K07 CA125588, Aim 2) to examine H. pylori genotypes and strain variation, with a novel approach. This study will take advantage of the existing research infrastructure located in the mountainous Copan region of western Honduras. Honduras has the highest incidence rates in Latin America and the western hemisphere, with estimated ASRs of 31.4 and 22.3 in males and females, respectively, based upon the IARC GLOBOCAN 2008 data released in 2010. The PI maintains a parallel epidemiology infrastructure in neighboring coastal Nicaragua, with relatively low incidence rates. Importantly, both populations are similar racially and ethnically, Hispanic Mestizo (95%), and without significant racial admixture (e.g., African). The primary goal of this study is to examine the phylogeographic origins of H. pylori by determination of ancestral haplotype with MLST in gastric cancer and chronic gastritis patients in a high incidence region of Central America and compare them with chronic gastritis patients in a neighboring low incidence region. The results from this study will provide critical data to support a novel approach, with the future goals of genomic and mechanistic studies, ultimately targeting biomarker development for the delineation of risk at the individual and the population level. The specific innovations in this proposal include: a) the examination of ancestral haplotypes in gastric cancer patients; b) comparison of ancestral haplotypes in similar Mestizo populations in high and low incidence regions of Central America, respectively, to avoid confounding by race/ethnicity; c) utilization of existing research infrastructures which the PI maintains; d) Hp strain determination in populations which account for a significant percentage of recent Hispanic immigrants in the U.S.