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

描述(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，这为加快科学研究和有针对性的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STRAI特有的遗传因素会影响患胃癌的风险，例如cagA和VacAs1m1基因。然而，很明显，需要确定其他细菌成分，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记物的话。最近的研究表明，根据哥伦比亚高发区和低发区慢性胃炎患者的研究，通过祖先单倍型多位点序列分型(MLST)确定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。这项建议是PI正在中美洲正在进行的胃癌流行病学倡议(K07 CA125588，AIM 2)的计划扩展，以用一种新的方法检查H.Pylori的基因类型和菌株变异。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。洪都拉斯在拉丁美洲和西半球的发病率最高，根据2010年发布的国际癌症研究中心GLOBOCAN2008年数据，估计男性和女性的ASR分别为31.4和22.3。PI在邻近的沿海尼加拉瓜维持着一个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是相似的，西班牙裔Mstizo(95%)，没有明显的种族混杂(例如，非洲人)。本研究的主要目的是通过MLST检测中美洲高发区胃癌和慢性胃炎患者的祖先单倍型，并与邻近低发区的慢性胃炎患者进行比较，以探讨Hp的系统地理起源。这项研究的结果将提供关键数据来支持 一种新的方法，未来的目标是基因组和机械学研究，最终以生物标记物的开发为目标，在个人和群体水平上描述风险。这项建议的具体创新包括：a)检查胃癌患者的祖先单倍型；b)比较中美洲高发区和低发区类似Mestizo人群的祖先单倍型，以避免因种族/民族而混淆；c)利用国际癌症研究所维持的现有研究基础设施；d)在美国最近的拉美裔移民中占很大比例的人群中Hp菌株的检测。

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.