Genome Wide Association Study of Head and Neck Cancer

描述（由申请人提供）：头颈癌与烟草和酒精接触有充分的证据，但只有一小部分使用者会患上这种疾病，这意味着遗传易感性的重要作用。因此，头颈癌是研究环境致癌物遗传易感性的良好模型。本R01应用程序的主要目标是对头颈癌病例和相应频率匹配对照进行全面的两阶段、高密度、全基因组单核苷酸多态性（SNP）分析，以确定头颈癌的新遗传危险因素。该建议建立在一个注释良好的现有病例和对照的DNA存储库上。我们研究的一个独特之处在于本研究中大多数病例和对照的DNA修复分析数据的可用性，这将使我们能够进行基因型/表型分析。我们还获得了来自同一来源人群的1200名白人对照受试者的全基因组关联数据。在目标1中，我们将使用370K Illumina Infinium HapMap HumanCNV370-Duo SNP芯片对1000例随机选择的头颈癌病例和500例对照进行基因分型。我们将在第一阶段使用结果变量作为病例对照状态和DNA修复能力测定数据进行关联分析（1000例和1700例对照）。我们的第二个目标是对第一阶段选择的snp进行第二阶段的分析，使用来自同一来源和加州大学洛杉矶分校的900个额外病例和相应的对照。我们将对来自第一个和第二个目标的病例和对照进行有效的联合分析，总共有1900例病例和2600例对照。最后，在目标3中，我们将应用新的统计工具，如潜在变量方法与Tukey的一自由度测试和支持向量机来识别基因-基因和基因-环境（使用吸烟和饮酒等环境因素）相互作用，从而导致头颈癌的风险。我们是一个经验丰富的调查团队，提供综合分析，包括流行病学，行为和功能数据。识别新的遗传危险因素及其与环境因素的相互作用将有助于头颈癌的早期诊断。公共卫生相关性：确定新的遗传风险因素及其与环境因素的相互作用将有助于疾病的早期诊断，并有助于根据个人暴露模式和遗传风险概况确定头颈癌发展风险最高的个体。

DESCRIPTION (provided by applicant): Head and neck cancers have well-documented associations with tobacco and alcohol exposure, but the disease develops in only a small fraction of users, which implies an important role for genetic susceptibility. Therefore, head and neck cancers are an excellent model for studying genetic susceptibility to environmental carcinogens. The primary goal of this R01 application is to perform a comprehensive two-stage, high-density, genome-wide single-nucleotide polymorphism (SNP) analysis of head and neck cancer cases and corresponding frequency matched controls to identify novel genetic risk factors for head and neck cancer. This proposal builds upon a well-annotated existing DNA repository of cases and controls. One of the unique features of our study is the availability of DNA repair assay data on most of the cases and controls in this study, which will allow us to conduct genotype/phenotype analyses. We also have access to genome-wide association data from 1200 white control subjects from the same source population. In aim 1, we will perform genotyping on 1000 randomly selected head and neck cancer cases and 500 controls using a 370K Illumina Infinium HapMap HumanCNV370-Duo SNP Chip. We will perform association analyses (1000 cases and 1700 controls) in the first stage using outcome variable as case-control status as well as DNA repair capacity assay data. Our second aim is to perform second-stage analysis of the SNPs selected in stage 1 using 900 additional cases and corresponding controls from the same source and from UCLA. We will use efficient joint analysis of cases and controls from the first and second aims, for a total of 1900 cases and 2600 controls. Finally, in aim 3, we will apply novel statistical tools such as the latent variable approach with Tukey's one-degree-of-freedom test and support vector machines to identify gene-gene and gene-environment (using environmental factors such as smoking and alcohol use) interactions that contribute to the risk of head and neck cancer. We are an experienced investigative team proposing a comprehensive analysis that incorporates epidemiological, behavioral, and functional data. Identification of novel genetic risk factors and their interactions with environmental factors will contribute to the early diagnosis of head and neck cancers. PUBLIC HEALTH RELEVANCE: The identification of novel genetic risk factors and their interactions with environmental factors will contribute to the early diagnosis of the disease and help identify individuals at highest risk for the development of head and neck cancer on the basis of their personal exposure patterns and their genetic risk profiles.