Genetic susceptibility to gastric cancer in Latin America

拉丁美洲胃癌的遗传易感性

• 批准号: 7458970
• 负责人: Eduardo M Tarazona-Santos
• 金额: $ 5.08万
• 依托单位: UNIVERSIDADE FEDERAL DE MINAS GERAIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458970
• 关键词: Acidity; Acids; Address; Adenocarcinoma; Admixture; Apoptosis; Appearance; Atrophic; Atrophic Gastritis; Biopsy Specimen; Brazil; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Carcinogens; Cells; Cessation of life; Chronic; Clinical; Clinical Data; Complex; Confounding Factors (Epidemiology); Data; Development; Disease; Dysplasia; Environmental Risk Factor; Enzymes; Epithelial Cell Proliferation; Epithelial Cells; Event; Gastric Adenocarcinoma; Gastric Intestinal Type Adenocarcinoma; Gastric Intraepithelial Neoplasia; Gastric Parietal Cells; Gastritis; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Goals; Haplotypes; Helicobacter Infections; Helicobacter pylori; High Prevalence; Histopathology; Human; IL8 gene; IL8RA gene; IL8RB gene; Immune response; Immunity; Incidence; Individual; Infection; Inflammatory; Inflammatory Response; Interleukin-8; Intestinal Metaplasia; Latin America; Lesion; Malignant Neoplasms; Measures; Mediating; Modeling; Molecular; Mutagenesis; PTGS2 gene; Pathogenesis; Patients; Pattern; Peru; Population; Predisposition; Premalignant; Principal Investigator; Production; Protocols documentation; Recruitment Activity; Risk; Role; Sampling; Somatic Mutation; South America; Staging; Stomach; Symptoms; TLR2 gene; TNF gene; Testing; Toll-Like Receptor 2; Toll-like receptors; Variant; angiogenesis; base; carcinogenesis; case control; cyclooxygenase 2; cytokine; genetic association; genetic epidemiology; genetic variant; malignant stomach neoplasm; model development; monocyte; neutrophil; pathogen; response

DESCRIPTION (provided by applicant): Gastric adenocarcinoma, the second cause of cancer-related deaths in Latin America, is associated with the high prevalence of infection with the type I carcinogen Helicobacter pylori. Several immunological events are associated with the inflammatory response in the stomach of infected individuals, which is associated with gastric carcinogenesis. This response is mediated by the Toll-like-receptors, pro-inflammatory cytokines such as interleukin-8 (IL8), 1L-1? and TNF-?, and the pro-inflammatory enzyme COX-2. Correa has proposed a progression model for the development of intestinal-type gastric adenocarcinoma, originally based on histopathology observations, but consistent with the effects of the pro-inflammatory immune response against H. pylori infection. However, there is substantial inter-individual variation in this progression, as well as in symptoms and clinical manifestations of carcinogenesis. Part of this variability is due to host genetic factors. The main goal of this proposal is to test the hypothesis that host genetic variants in TLR2, COX2, IL1B, ILRB, IL8 and IL8RA which are key components of the immune response against H. pylori infection, are associated with susceptibility to gastric adenocarcinoma in Peruvian and Brazilian admixed populations. We propose to perform a case-control association to with the following specific aims: (1) To collect clinical data and DMA samples of 860 gastric adenocarcinoma patients and 860 controls, 500 matched pairs from Lima (Peru) and 360 matched pairs from Rio de Janeiro (Brazil). (2) To quantify the levels of COX-2 and IL-8 in the stomach of gastric cancer patients and in a subset of controls by immunohistochemical analysis of biopsy specimens. (3) To identify the most informative set of tag-SNPs in TLR2, COX2, IL1B, ILRB, IL8, IL8RA and IL8RB to be used in genetic association studies in the selected populations and (4) To test the statistical association among haplotypes of TLR2, COX2, IL1B, ILRB, IL8 and IL8RA and: (a) levels of IL-8 and COX-2 in the stomach and (b) gastric adenocarcinoma, controlling for the effect of potential confounding variables such as admixture. We propose to develop a multi-centric study using a gene-candidate approach, capitalizing data demonstrating the role of the selected genes in the pathogenesis of gastric adenocarcinoma. By performing the study in Lima and Rio de Janeiro, we address the key issue of replication of genetic association studies.

描述（由申请人提供）：胃腺癌是拉丁美洲与癌症相关死亡的第二个原因，与I型癌型幽门螺杆菌的高感染率有关。几个免疫事件与感染个体的胃中的炎症反应有关，这与胃癌发生有关。这种反应是由促炎细胞因子（例如白介素-8（IL8），1L-1）介导的。和TNF-？和促炎酶COX-2。科雷亚（Correa）提出了一个进展模型，用于开发肠道胃腺癌的发展，最初是基于组织病理学观察到的，但与促炎症性幽门螺杆菌感染的促炎性免疫反应的影响一致。但是，这种进展以及癌变的症状和临床表现存在很大的个体差异。这种变异的一部分是由于宿主遗传因素引起的。该提案的主要目的是检验以下假设：TLR2，COX2，IL1B，ILRB，IL8和IL8RA中的宿主遗传变异是针对幽门螺杆菌感染的免疫反应的关键组成部分，与对胃腺癌对佩里氏症和巴西脂肪症的易感性有关。我们建议与以下特定目的进行病例对照关联：（1）收集860例胃腺癌患者和860个对照组的临床数据和DMA样品，来自利马（秘鲁）的500对匹配和360对匹配的对，来自巴西Rio de Janeiro（巴西）。 （2）通过对活检标本的免疫组织化学分析来量化胃癌患者胃的COX-2和IL-8水平。 (3) To identify the most informative set of tag-SNPs in TLR2, COX2, IL1B, ILRB, IL8, IL8RA and IL8RB to be used in genetic association studies in the selected populations and (4) To test the statistical association among haplotypes of TLR2, COX2, IL1B, ILRB, IL8 and IL8RA and: (a) levels of IL-8 and胃中的COX-2和（b）胃腺癌，控制潜在混杂变量（例如混合）的影响。我们建议使用基因候选方法进行多中心研究，并资本化数据，证明了所选基因在胃腺癌发病机理中的作用。通过在利马和里约热内卢进行研究，我们解决了遗传关联研究复制的关键问题。