Molecular Epidemiology of Head and Neck Cancer

描述（由申请人提供）：吸烟和饮酒是 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， 一般人群的亚群在遗传上易患SCCHN。我们 假设遗传易感性在SCCHN病因学中起作用 遗传易感性和暴露于 烟草和酒精。为了验证这一假设，我们建议进行分子 流行病学病例对照研究（800例病例和800例对照）， 选择的表型和基因型标记之间的关联遗传 发展SCCHN的易感性和风险，并寻找潜在的 SCCHN中的基因-环境相互作用。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 新诊断的SCCHN患者在M. D.安德森癌症中心和控制 将是年龄、性别和种族匹配的健康受试者， 基因无关的医院访客控制目标2：确定主要 选定的遗传易感性生物标志物对SCCHN风险的影响， 提出了一组开发良好的体外功能测定：A.表型 DNA修复能力（DRC）：该表型将通过（1）宿主细胞 再活化（HCR）测定以测量宿主细胞去除加合物的能力 在质粒DNA中（一种报告基因），用苯并-a-芘二醇环氧化物（BPDE）诱导; (2)体外诱导的DNA加合物测定，以测量BPDE诱导的DNA加合物的水平。 基因组DNA中的加合物;和（3）突变敏感性测定，以测量 BPDE诱导的染色体畸变频率。这三种表型 我们实验室新开发的检测将使用外周血细胞进行， 来自500例病例和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性： 对800例患者进行GSTMI、GSTTI、GSTPI、ADH 3、XPD、XPC和XRCCI检测 和800个对照，使用基于聚合酶链反应（PCR）的基因组DNA 技术.因此，DNA修复表型和基因型的相关性将 估计（500例病例和500例对照）。目标3：确定 修饰/联合效应和/或基因-环境相互作用 暴露于烟草/酒精和SCCHN中选择基因的基因型。我们将 测试假设，那些既有暴露又有 不良基因型患者发生SCCHN的风险升高。这一目标将是 完成了800例病例和800例对照。 我们相信这项研究将推动 我们对SCCHN遗传易感性的了解，这些遗传易感性的生物标志物 易感性最终将有助于识别高风险的个体， 发展烟草/酒精相关的癌症，然后可以针对 癌症预防计划，包括初级预防和临床 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.