Molecular Epidemiology of Head and Neck Cancer

描述(申请人提供)：吸烟和饮酒情况： 头颈部鳞状细胞癌的主要危险因素 (SCCHN)。然而，只有一小部分吸烟者会患上SCCHN，这表明 一般人群中的亚群在遗传上对SCCHN易感。我们 假设遗传易感性在SCCHN的病因中起作用 在遗传易感性和暴露于 烟和酒。为了验证这一假设，我们建议进行一种分子 流行病学病例对照研究(800例病例和800例对照) 遗传相关表型标记和遗传型标记之间的相关性 SCCHN的易感性、风险性及寻找潜质 SCCHN中的基因-环境交互作用。我们的具体目标是：目标1： 建立全面的流行病学和临床数据库。案件将会是 M.D.安德森癌症中心新诊断的SCCHN患者和对照组 将是年龄、性别和种族匹配的健康受试者，从 与基因无关的医院访客控制。目标2：确定主要的 选定的遗传易感性生物标记物对SCCHN风险的影响 提出了一系列成熟的体外功能检测方法：a.表型 DNA修复能力(DRC)：这种表型将通过(1)宿主细胞进行评估 再激活(HCR)试验测量宿主细胞去除加合物的能力 在苯并-a-芘二醇环氧化物(BPDE)诱导的报告基因DNA中； (2)体外诱导DNA加合物法检测BPDE诱导的DNA加合物水平 基因组DNA中的加合物；(3)诱变剂敏感性试验 BPDE诱发的染色体畸变率。这三种表型 我们实验室新开发的分析将使用外设进行 500例患者和500例对照的淋巴细胞以评估遗传易感性 SCCHN.B.代谢和DNA修复基因的遗传多态： 对800例患者进行GSTMI、GSTTI、GSTPI、ADH3、XPD、XPC、XRCCI测定 以聚合酶链式反应(PCR)为基础使用基因组DNA的800名对照 技巧。因此，DNA修复表型和基因型的相关性将 估计(在500个病例和500个对照中)。目标3：确定 基因修饰/联合效应和/或基因-环境互作 烟酒暴露与SCCHN基因分型的关系我们会 检验这样一种假设，即那些既有接触又有 不良基因携带者患SCCHN的风险较高。这一目标将是 完成了800个病例和800个对照。我们相信这项研究将会取得进展 我们对SCCHN遗传易感性的了解以及这些基因的生物标记物 易感性最终将有助于识别高危人群。 患上与烟草/酒精相关的癌症，然后可能成为目标 癌症预防计划，包括初级预防和临床预防 第二原发癌的化学预防。

DESCRIPTION (provided by applicant): Tobacco use and alcohol consumption are the major risk factors for squamous cell carcinoma of the head and neck (SCCHN). However, only a fraction of smokers develop SCCHN, which suggests that subgroups of the general population are genetically susceptible to SCCHN. We hypothesize that genetic susceptibility plays a role in the etiology of SCCHN and that there is an interaction between genetic susceptibility and exposure to tobacco and alcohol. To test this hypothesis, we propose to conduct a molecular epidemiological case-control study (800 cases and 800 controls) to investigate the associations between selected phenotypic and genotypic markers of genetic susceptibility and risk of developing SCCHN and search for potential gene-environment interactions in SCCHN. Our specific aims are: Aim 1: To construct a comprehensive epidemiological and clinical database. Cases will be newly diagnosed SCCHN patients at M. D. Anderson Cancer Center and controls will be age-, sex-, and ethnicity-matched healthy subjects identified from genetically unrelated hospital visitor controls. Aim 2: To determine the main effects of the selected biomarkers for genetic susceptibility on risk of SCCHN, a panel of well-developed in vitro functional assays is proposed: A. Phenotypic DNA repair capacity (DRC): This phenotype will be assessed by (1) Host-cell reactivation (HCR) assay to measure the host cell's ability to remove adducts in plasmid DNA (a reporter gene) induced by benzo-a-pyrene diol epoxide (BPDE); (2) In vitro induced DNA adduct assay to measure the levels of BPDE-induced adducts in genomic DNA; and (3) Mutagen sensitivity assay to measure the frequency of BPDE-induced chromosomal aberrations. These three phenotypic assays newly developed in our laboratory will be performed using peripheral lymphocytes from 500 cases and 500 controls to assess genetic susceptibility to SCCHN. B. Genetic polymorphisms of metabolic and DNA repair genes: Genotypes of GSTMI, GSTTI, GSTPI, ADH3, XPD, XPC and XRCCI will be determined in 800 cases and 800 controls using genomic DNA by polymerase chain reaction (PCR)-based techniques. As a result, the DNA repair phenotype and genotype correlation will be estimated (in 500 cases and 500 controls). Aim 3: To determine the modification/joint effects and/or gene-environment interactions between exposure to tobacco/alcohol and genotypes of select genes in SCCHN. We will test the hypothesis that those individuals who have both the exposure and an adverse genotype are at elevated risk of developing SCCHN. This aim will be accomplished with 800 cases and 800 controls. We believe this study will advance our knowledge of genetic susceptibility to SCCHN and that these biomarkers for genetic susceptibility will eventually help identify individuals at high risk of developing tobacco/alcohol-related cancer, who could then be targeted for cancer prevention programs, including primary prevention and clinical chemoprevention for second primary cancers.