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

描述（由申请人提供）：胃癌是全球感染相关癌症死亡的主要原因，总体上是癌症死亡的第二大原因。预计在短期内，它将上升到全因死亡率的第八位。胃癌具有明显的地理变异性，高发地区包括拉丁美洲和东亚，这为加速科学调查和集中干预计划提供了机会。 幽门螺杆菌（Helicobacter pylori，Hp）是胃癌的主要危险因素。许多品系特异性遗传因素影响胃癌风险，如cagA和vacAs 1 m1基因型。然而，很明显，需要鉴定其他细菌成分以更好地理解致癌机制并解释个体和群体风险的差异，特别是如果要开发生物标志物。最近的研究表明，H。pylori的地理起源，如多位点序列分型（MLST）的祖先单倍型所确定的，可能有助于描述H。幽门螺杆菌相关的癌症风险，基于对哥伦比亚高和低发病率地区慢性胃炎受试者的研究。 该提案是PI正在进行的中美洲胃癌流行病学倡议（K 07 CA 125588，目标2）的计划扩展，以检查H。pylori基因型和菌株变异的研究。这项研究将利用位于洪都拉斯西部山区科潘的现有研究基础设施。洪都拉斯是拉丁美洲和西半球发病率最高的国家，根据2010年发布的IARC GLOBOCAN 2008年数据，估计男性和女性的ASR分别为31.4和22.3。PI在邻近的尼加拉瓜沿海地区保持着平行的流行病学基础设施，发病率相对较低。重要的是，这两个群体在种族和民族上相似，西班牙裔混血儿（95%），没有明显的种族混合（例如，非洲）。 本研究的主要目的是探讨H.在中美洲高发区的胃癌和慢性胃炎患者中，通过MLST确定祖先单倍型来检测pylori，并将其与邻近低发病率地区的慢性胃炎患者进行比较。这项研究的结果将提供关键数据，以支持 这是一种新的方法，未来的目标是基因组和机制研究，最终目标是生物标志物的发展，以描绘个人和群体水平的风险。 该提案的具体创新包括：a）胃癌患者的祖先单倍型检查; B）分别比较中美洲高发病率和低发病率地区相似的梅斯蒂索人群体的祖先单倍型，以避免种族/民族混淆; c）利用PI维护的现有研究基础设施; d）在占美国最近西班牙裔移民的显著百分比的人群中的Hp菌株测定。

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.