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

幽门螺杆菌祖先单倍型是拉丁美洲胃癌风险决定因素

• 批准号: 8633019
• 负责人: Douglas Morgan
• 金额: $ 7.57万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633019
• 关键词: Accounting; Adenocarcinoma; Admixture; Affect; African; Age; Area; Atrophic; Atrophic Gastritis; Biological Markers; Biopsy; Cancer Etiology; Cancer Patient; Cell Nucleus; Central America; Cessation of life; Chronic Gastritis; Colombia; DNA; DNA Damage; Data; Developing Countries; Development; Diet; Dysplasia; Epidemiology; Epithelial; Epithelial Cells; Ethnic Origin; European; Far East; Female; Future; Gastric Adenocarcinoma; Gastric Intestinal Type Adenocarcinoma; Gastritis; Gastrointestinal Diseases; Genetic; Genomics; Genotype; Goals; Haplotypes; Helicobacter Infections; Helicobacter pylori; Hispanics; Histology; Histopathology; Honduras; Immigrant; Immune response; Incidence; Indigenous; Individual; International Agency for Research on Cancer; Intervention; Intestinal Metaplasia; Investigation; Latin America; Mucositis; Mucous Membrane; Nicaragua; Oncogenic; Patients; Population; Prevalence; Prevention; Prevention program; Race; Research Infrastructure; Risk; Risk Factors; Series; Severities; Staging; Stomach; Study Subject; Subgroup; Testing; Variant; Virulent; Work; base; cancer epidemiology; cancer risk; geographic difference; high risk; infection related cancer; innovation; intervention program; male; malignant stomach neoplasm; mortality; novel; novel strategies; oxidative DNA damage; public health relevance; screening

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.

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，总体而言是癌症死亡的第二大原因。预计近期全因死亡率将上升至第八。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。许多特定的遗传因素会影响胃癌风险，例如 cagA 和 vacAs1m1 基因型。然而，很明显，需要鉴定其他细菌成分，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志物的话。最近的研究表明，基于对哥伦比亚高发区和低发区慢性胃炎受试者的研究，通过多位点序列分型 (MLST) 的祖先单倍型确定的幽门螺杆菌系统发育地理起源可能有助于描述幽门螺杆菌相关的癌症风险。 该提案是 PI 在中美洲正在进行的胃癌流行病学计划（K07 CA125588，目标 2）的计划扩展，以采用一种新颖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。洪都拉斯的发病率是拉丁美洲和西半球最高的，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。PI 在邻国沿海尼加拉瓜维持着平行的流行病学基础设施，发病率相对较低。重要的是，这两个人口在种族和民族上都很相似，西班牙裔混血儿 (95%)，并且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 MLST 测定中美洲高发地区胃癌和慢性胃炎患者的祖先单倍型来检查幽门螺杆菌的系统发育地理起源，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数据来支持 一种新颖的方法，其未来目标是基因组和机制研究，最终针对生物标志物开发，以描述个人和群体水平的风险。 该提案的具体创新点包括：a）胃癌患者祖先单倍型的检查； b) 分别比较中美洲高发区和低发区类似混血人口的祖先单倍型，以避免种族/族裔造成的混淆； c) 利用 PI 维护的现有研究基础设施； d) 在美国近期拉美裔移民中占很大比例的人群中进行 Hp 菌株测定