Comprehensive Assessment of Bladder Cancer Genetic Susceptibility

描述（由申请人提供）：2004年，美国有98,400人被诊断为膀胱癌，12,710人死于该疾病。在美国，新英格兰北部（包括新罕布什尔州）是膀胱癌死亡率最高的地区之一。对单个snp和癌症易感性的流行病学研究表明，某些遗传多态性（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，还没有膀胱癌的大规模研究将单倍型、基因-基因和基因-环境相互作用纳入对关键癌症控制过程基因变异的综合评估。已完成的基于父母人群的新罕布什尔州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。使用最近设计的具有成本效益的癌症基因分型面板，我们建议测试大约542例病例和585例对照，在大约250个癌症易感基因中检测1536个编码和单倍型标记单核苷酸多态性（snp）。我们将使用传统的逻辑回归方法和新开发的方法来评估基因-基因和基因-环境相互作用，即多因素降维（MDR）和橙色画布中的交互图函数。我们将把我们的初步分析工作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个基因上。分析将首先进行推断的单倍型和编码snp。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减少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来设计个性化治疗方案。拟议研究与公共卫生的相关性：本研究项目将使用新开发的分析工具来有效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物暴露后个体间风险差异的遗传基础。

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.