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）：胃腺癌是拉丁美洲癌症相关死亡的第二大原因，与I型致癌物幽门螺杆菌感染的高患病率有关。几种免疫学事件与感染个体的胃中的炎症反应相关，这与胃癌发生相关。这种反应是介导的Toll样受体，促炎细胞因子，如白细胞介素-8（IL-8），IL-1？和TNF-？，和促炎酶考克斯-2。Correa提出了一种胃粘膜型胃腺癌发展的进展模型，最初是基于组织病理学观察，但与促炎性免疫反应对H.幽门感染然而，在这种进展中，以及在癌发生的症状和临床表现中，存在大量的个体间差异。这种变异性的一部分是由于宿主的遗传因素。本研究的主要目的是验证宿主TLR 2、COX 2、IL 1B、ILRB、IL 8和IL 8 RA的遗传变异是抗H. pylori感染与秘鲁和巴西混合人群中胃腺癌的易感性相关。本研究拟进行病例对照研究，具体目的如下：（1）收集860例胃腺癌患者和860例对照的临床资料和DMA样本，其中500对来自利马（秘鲁），360对来自里约热内卢（巴西）。(2)通过对活检标本进行免疫组化分析，定量胃癌患者和对照组胃中考克斯-2和IL-8的水平。(3)鉴定TLR 2、COX 2、IL 1B、ILRB、IL 8、IL 8 RA和IL 8 RB中信息量最大的tag-SNP组，以用于所选人群的遗传关联研究，以及（4）检验TLR 2、COX 2、IL 1B、ILRB、IL 8和IL 8 RA的单倍型之间的统计关联，以及：（a）胃和（B）胃腺癌中IL-8和考克斯-2的水平，控制潜在混杂变量如混合物的影响。我们建议使用基因候选方法开展一项多中心研究，利用数据证明所选基因在胃腺癌发病机制中的作用。通过在利马和里约热内卢进行研究，我们解决了复制遗传关联研究的关键问题。