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，它将在全因死亡率中上升到第八位。胃癌具有明显的地理差异，高发地区包括拉丁美洲和东亚，这为加速科学调查和重点干预计划提供了机会。幽门螺杆菌（Hp）是胃癌的主要危险因素。许多菌株特异性遗传因素影响胃癌风险，如cagA和vacAs1m1基因型。然而，很明显，需要识别其他细菌成分，以更好地了解致癌机制，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，通过多位点序列分型（MLST）确定的祖先单倍型，幽门螺杆菌的系统地理起源可能有助于描述幽门螺杆菌相关的癌症风险，这是基于对哥伦比亚高发病率和低发病率地区慢性胃炎患者的研究。该提案是PI正在进行的中美洲胃癌流行病学倡议（K07 CA125588, Aim 2）的计划扩展，以一种新的方法检查幽门螺杆菌基因型和菌株变异。这项研究将利用位于洪都拉斯西部科潘山区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数据，估计男性和女性的asr分别为31.4和22.3。该方案在发病率相对较低的邻近沿海尼加拉瓜维持一个平行的流行病学基础设施。重要的是，这两个人群在种族和民族上是相似的，西班牙混血儿（95%），没有明显的种族混合（例如，非洲人）。本研究的主要目的是通过测定中美洲高发地区胃癌和慢性胃炎患者中具有MLST的祖先单倍型来研究幽门螺杆菌的系统地理起源，并将其与邻近低发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的数据来支持

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.