International Case Control Study of Malignant Glioma

恶性胶质瘤国际病例对照研究

• 批准号: 8464531
• 负责人: MELISSA L. BONDY
• 金额: $ 186.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-18 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464531
• 关键词: Accounting; Address; Adult Glioma; Age; Age of Onset; Asthma; Bioinformatics; Biological; California; Case-Control Studies; Cessation of life; Classification; Collection; DNA Repair; Data; Data Set; Databases; Disease; Doctor of Medicine; Ensure; Environment; Epidemiology; Ethnic Origin; European; Exposure to; Family; First Degree Relative; Funding; Gender; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glioblastoma; Glioma; Haplotypes; Heterogeneity; Histologic; Histopathology; Hypersensitivity; Infection; Inflammation; Inherited; International; Ionizing radiation; Left; Machine Learning; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Manuscripts; Medical History; Mining; Modeling; Newly Diagnosed; Pathway interactions; Phase; Play; Predisposition; Primary Brain Neoplasms; Recording of previous events; Recruitment Activity; Research Infrastructure; Risk; Role; Sample Size; Sampling; San Francisco; Series; Site; Specimen; Staging; Susceptibility Gene; Syndrome; Testing; The Cancer Genome Atlas; Trees; Trust; Universities; Validation; Variant; base; cancer site; case control; cohort; density; epidemiologic data; forest; functional genomics; genetic association; genetic epidemiology; genetic variant; genome wide association study; high risk; immune function; international center; member; novel; population based; programs; public health relevance; success; tool; tumor

DESCRIPTION (provided by applicant): Glioma comprises about 40% of all primary brain tumors accounting for as many as 26,000 U.S. and European deaths annually. Inherited susceptibility plays a role with 2-fold increased risk of glioma among first-degree relatives of glioma cases. We initiated a multi-center, international linkage study: "Genetic Epidemiology of Glioma International Consortium" in 2007 to address the role of inherited susceptibility. Since this study does not allow us currently to address the role of genetic susceptibility in sporadic cases, we propose this case- control study to address this gap. Members of the consortium have conducted genome wide association studies (GWAS) that will be the discovery phase (phase I). While of high value for discovery, we propose to recruit 6,000 newly diagnosed glioma cases and 6,000 age-gender-ethnicity-matched controls, and collect detailed epidemiologic data and biologic samples from the 13 participating Gliogene sites. We hypothesize that novel inherited variation influencing the susceptibility to glioma can be identified by high density SNP analysis, and propose the following specific aims: SA1: Identify common genetic variants contributing to the risk of glioma. We plan to conduct phases 2 and 3 of the 3 phase approach, specifically we will: (SA1a) Validate GWAS findings from the discovery sets, and replicate the top hits (~23,000 SNPs) with lowest p- values from the two phase GWA studies in a series of 2,000 cases and 2,000 controls (phase 2, validation). Validate the top hits from the test set (aim 1a). From stage 2, genes with SNPs displaying an association at pd10-4 (including the complete haplotype tagging - approximately 100 SNPs) will then be genotyped in a further series of 4,000 cases and 4,000 controls (stage 3, validation). SNPs significant at 10-7 or better will be considered in the final analyses. (SA1b). Using an a priori hypothesis that DNA repair in inflammation contribute to glioma risk, we will selectively interrogate DNA repair and inflammation pathway genes using data for select genes derived from the high-density array. We will conduct a hypothesis driven genetic association in DNA repair and in inflammation/immune function related genes with glioma risk using functional genomic and bioinformatic tools to interrogate available databases. (SA2): Evaluate gene-gene (G-G) and gene- environmental (G-E) interactions with strong biologic relevance to identify G-G and G-E interactions for glioma risk using machine-learning tools (MDR, FITF, and CART) in these exploratory analyses. There are no existing glioma case-control studies with sufficient numbers of biological samples and common epidemiologic data to conduct a comprehensive validation and replication study, or to address the issues of tumor heterogeneity as we will in this study.

描述（由申请人提供）：胶质瘤约占所有原发性脑肿瘤的40％，每年多达26,000例美国和欧洲死亡。在神经胶质瘤病例的一级亲属中，遗传易感性起作用，伴有胶质瘤风险增加了2倍。我们于2007年发起了一项多中心国际联系研究：“神经胶质瘤国际联盟的遗传流行病学”，以解决遗传易感性的作用。由于这项研究不允许我们当前解决遗传易感性在零星病例中的作用，因此我们建议该病例控制研究以解决这一差距。财团的成员已经进行了基因组广泛的关联研究（GWAS），这将是发现阶段（I阶段）。虽然有很高的发现价值，但我们建议从13个参与的神经胶条地点招募6,000例新诊断的神经胶质瘤病例和6,000例与年龄种族匹配的对照，并收集详细的流行病学数据和生物学样本。我们假设可以通过高密度SNP分析来识别影响对神经胶质瘤易感性的新遗传变异，并提出以下特定目的：SA1：确定有助于神经胶质瘤风险的常见遗传变异。我们计划在3期方法中进行第2阶段和第3阶段，具体来说：（SA1A）从发现集中验证GWAS的发现，并在两期GWA研究中以最低p值的最低命中（约23,000个SNP）复制一系列2,000例Case and 2,000 Case和2,000个对照（阶段2，验证）。从测试集（AIM 1A）中验证最高点击。从阶段2中，具有SNP的基因在PD10-4处显示关联（包括完整的单倍型标记 - 大约100个SNP），然后将在另一系列4,000个病例和4,000个对照组（第3阶段，验证）中进行基因分型。在最终分析中，将考虑在10-7或更高的SNP。 （SA1B）。使用先验假设，即炎症中的DNA修复有助于神经胶质瘤风险，我们将使用来自高密度阵列的精选基因选择性地询问DNA修复和炎症途径基因。我们将使用功能基因组和生物信息学工具在DNA修复以及与神经胶质瘤风险的炎症/免疫功能相关基因中进行假设驱动的遗传关联，以询问可用的数据库。 （SA2）：评估基因基因（G-G）和基因环境（G-E）相互作用具有强大的生物学相关性，以在这些探索性分析中使用机器学习工具（MDR，FITF和TART）来识别G-G-G和G-E相互作用，以识别Glioma风险的G-G和G-E相互作用。没有现有的神经胶质瘤病例对照研究，具有足够数量的生物样品和常见的流行病学数据来进行全面的验证和复制研究，或者像我们在本研究中一样解决了肿瘤异质性问题。