Comprehensive Assessment of Bladder Cancer Genetic Susceptibility

膀胱癌遗传易感性综合评估

• 批准号: 7201555
• 负责人: Angeline Sanderson Andrew
• 金额: $ 7.76万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201555
• 关键词: Apoptosis; Apoptotic; BCL6 gene; Bladder; Bladder Diseases; CDKN1A gene; CYP1B1 gene; CYP2D6 gene; CYP2E1 gene; Cancer Control; Cancer-Predisposing Gene; Carcinogen exposure; Case-Control Studies; Cell Cycle Checkpoint; Cell Cycle Regulation; Cells; Cessation of life; Chemicals; Chemoprevention; Chronic; Code; Constitutional; DNA Damage; Data; Diagnosis; Diagnostic; Disease; Disruption; Drug Metabolic Detoxication; Enzymes; Epidemiologic Studies; Evaluation; Exposure to; Future; GSTM1 gene; GSTP1 gene; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Graph; Haplotypes; IL8 gene; Immunologics; Incidence; Individual; Infection; Inflammation; Inflammatory; Interleukin-10; Interleukin-15; Interleukin-7; Logistic Regressions; MTHFR gene; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Metabolism; Methods; Methylenetetrahydrofolate reductase (NADPH); Molecular; NAT2 gene; New England; New Hampshire; Numbers; Occupational; Oranges; Organ; Parents; Pathway interactions; Population; Predisposition; Premalignant; Process; Processed Genes; Public Health; Rate; Recording of previous events; Regulatory Pathway; Research; Research Project Grants; Risk; Role; Single Nucleotide Polymorphism; Smoking; Specimen; TNFRSF10A gene; TP53 gene; Testing; Treatment Protocols; Variant; Vascular Endothelial Growth Factors; Xenobiotics; base; cancer cell; cancer genetics; cancer risk; cancer site; carcinogenesis; caspase-9; cost; design; gene environment interaction; gene interaction; genetic risk factor; glutathione S-transferase M1; glutathione S-transferase pi; heterocyclic aromatic amines; irritation; male; mortality; oncoprotein p21; tobacco exposure; tool; trait; tumor growth

DESCRIPTION (provided by applicant): In 2004, 98,400 people in the U.S. were diagnosed with bladder cancer, 12,710 died of the disease. Within the US, Northern New England (including New Hampshire) has among the highest bladder cancer mortality rates. Epidemiologic studies that examined single SNPs and cancer susceptibility indicate modifying effects of certain genetic polymorphisms (e.g., NAT2). However, results for a number of polymorphisms are inconsistent. As yet no large-scale studies of bladder cancer have incorporated haplotype, gene-gene and gene-environment interactions in a comprehensive evaluation of variations in critical cancer control process genes. The completed parent population-based case-control study of bladder cancer incidence in New Hampshire has collected detailed exposure history and biologic specimens. Using a recently designed, cost-effective, genotyping panel for cancer, we propose to test approximately 542 cases and 585 controls for 1536 coding and haplotype tagging single nucleotide polymorphisms (SNPs) in approximately 250 cancer susceptibility genes. We will use both traditional logistic regression methods and newly developed methods for evaluating gene-gene and gene-environment interactions, i.e., Multifactor Dimensionality Reduction (MDR) and the Interaction Graph function in Orange Canvas. We will focus our initial analysis efforts on 48 genes in four important cancer regulatory pathways (the detoxification, cell cycle checkpoint, apoptosis, and inflammatory pathways). Analysis will be first be performed on inferred haplotypes and coding SNPs. We will then evaluate gene-gene and gene-environment interactions. Identifying the genetic and exposure factors that influence the risk of bladder cancer will provide critical information to reduce bladder cancer incidence and will facilitate chemoprevention efforts and the use of molecular diagnostic tools to design individualized treatment regimens. Relevance Of The Proposed Research To Public Health: This research project will use newly developed analysis tools to efficiently identify genetic risk factors for bladder cancer. We will also investigate the genetic basis for the inter-individual variation in risk following carcinogenic exposures including smoking.

描述(申请人提供)：2004年，美国有98,400人被诊断患有膀胱癌，其中12,710人死于膀胱癌。在美国，新英格兰北部(包括新汉普郡)是膀胱癌死亡率最高的地区之一。检测单个SNPs和癌症易感性的流行病学研究表明，某些基因多态(如NAT2)具有修饰作用。然而，许多多态性的结果是不一致的。到目前为止，还没有大规模的膀胱癌研究将单倍型、基因-基因和基因-环境相互作用纳入到关键癌症控制过程基因变异的综合评估中。新汉普郡已完成的基于父母人群的膀胱癌发病率病例对照研究收集了详细的暴露史和生物标本。使用最近设计的、经济有效的癌症基因分型小组，我们建议测试大约542个病例和585个对照，以检测大约250个癌症易感基因中的1536个编码和单倍型标记单核苷酸多态(SNPs)。我们将使用传统的Logistic回归方法和新开发的方法来评估基因-基因和基因-环境的交互作用，即多因素降维(MDR)和橙色画布中的交互作用图函数。我们将集中在四个重要的癌症调控途径(解毒、细胞周期检查点、细胞凋亡和炎症途径)中的48个基因进行初步分析。将首先对推断的单倍型和编码SNP进行分析。然后我们将评估基因-基因和基因-环境的相互作用。确定影响膀胱癌风险的遗传和暴露因素将为降低膀胱癌发病率提供关键信息，并将促进化学预防工作和使用分子诊断工具设计个性化治疗方案。拟议研究与公共健康的相关性：这项研究项目将使用新开发的分析工具来有效地识别膀胱癌的遗传风险因素。我们还将调查包括吸烟在内的致癌暴露后风险个体间差异的遗传基础。