Human HNSCC: CYP1B1/1A1/1A2 and AHR Gene Polymorphisms

人类 HNSCC：CYP1B1/1A1/1A2 和 AHR 基因多态性

• 批准号: 7392834
• 负责人: Daniel W. Nebert
• 金额: $ 20万
• 依托单位: UNIVERSITY OF CINCINNATI
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392834
• 关键词: Affinity; Alleles; Animals; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Binding; Blood; CYP1A1 gene; CYP1A2 gene; CYP1B1 gene; Chemicals; Cigarette; Classification; Clinical; Cultured Cells; Cytochrome P450; DNA; Data; Databases; Dioxins; Employee Strikes; Enzymes; Epidemiologist; Epithelial Cells; Exons; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Haplotypes; Head and Neck Squamous Cell Carcinoma; High-Risk Cancer; Human; In Vitro; Individual; Intervention; Knockout Mice; Malignant Neoplasms; Metabolic Activation; Morbidity - disease rate; Nitrosamines; Oral cavity; Patient Care; Patients; Phenotype; Polycyclic Hydrocarbons; Population; Prevention intervention; Process; Proteins; Receptor Gene; Recording of previous events; Reporting; Research Personnel; Resistance; Risk; Site; Smoker; Subgroup; Untranslated Regions; Variant; aromatic hydrocarbon receptor; cancer risk; cigarette smoke-induced; cigarette smoking; cigarette smoking; cohort; cost; detoxication; enzyme activity; genotoxicity; human data; mortality; programs; response; trait; ward

DESCRIPTION (provided by applicant): Cytochromes P450 1B1, 1A1 & 1A2 (CYP1B1, CYP1A1, and CYP1A2) are responsible for both detoxifying and metabolically activating innumerable polycyclic aromatic hydrocarbons (PAHs), nitrosamines, and A/-heterocyclics present in combustion processes including cigarette smoke. The PAH- inducible CYP1B1/1A1/1A2 genes are up-regulated by the aromatic hydrocarbon receptor (AHR). Many in vitro, cell culture and animal studies have shown that high CYP1 enzyme levels and AHR high-affinity are correlated with increased genotoxicity caused by PAHs; recent studies with knockout mice, however, show that, whereas high CYP1B1 activity causes metabolic activation, CYP1A1 and CYP1A2 are far more important in detoxication than metabolic activation. Data in humans have been inconclusive, perhaps because many are assuming that all three CYP1 enzymes cause only higher cancer risk. We have a large cohort of head-and-neck squamous-cell carcinoma (HNSCC) patients with a history of one to 40 cigarette pack-years ("highly sensitive," HS) and heavy smokers with >80 pack-years having no cancer ("highly resistant," HR)?strongly suggesting a genetic component. These two extremes will be studied, using the extreme discordant phenotype (EDP) approach. A systematic search (SNP-discovery followed by SNP- typing) for haplotypes of the human,CYP1B1 and AHR genes is now possible; we have completed such a study of the CYP1A1_1A2 locus (39.6 kb) and discovered 85 SNPs, 49 of which were not yet in any database. Our hypothesis is: Specific haplotypes involving one or more of these four genes leading to high CYP1B1 and low CYP1A1/1A2 activities are associated with increased risk of HNSCC cancer in smokers. In the 3 years of this proposed project, we therefore will: [a] carry out whatever SNP-discovery and SNP-typing that still needs to be done, from six major geographically-isolated subgroups; we will collect blood and prepare DMA from 200 HS HNSCC patients and 200 HR non-cancer heavy smokers in our cohort; and [b] examine the association between haplotypes and risk of HNSCC by performing SNP-typing of the CYP1B1, CYP1A1, CYP1A2 and AHR genes in the 200 HS versus the 200 HR individuals. Establishing important phenotype-genotype associations between HNSCC and these four genes would provide the first unequivocal data that humans are similar to laboratory animals regarding cancer and one or more of these genes.

描述（由申请人提供）：细胞色素 P450 1B1、1A1 和 1A2（CYP1B1、CYP1A1 和 CYP1A2）负责解毒和代谢激活燃烧过程（包括香烟烟雾）中存在的无数多环芳烃 (PAH)、亚硝胺和 A/-杂环化合物。 PAH 诱导型 CYP1B1/1A1/1A2 基因受芳香烃受体 (AHR) 上调。许多体外、细胞培养和动物研究表明，高 CYP1 酶水平和 AHR 高亲和力与 PAH 引起的遗传毒性增加相关；然而，最近对基因敲除小鼠的研究表明，虽然高 CYP1B1 活性会导致代谢激活，但 CYP1A1 和 CYP1A2 在解毒方面比代谢激活更重要。人类数据尚无定论，也许是因为许多人假设所有三种 CYP1 酶只会导致更高的癌症风险。我们有一大群头颈鳞状细胞癌 (HNSCC) 患者，其吸烟史为 1 至 40 包年（“高度敏感”，HS），以及吸烟超过 80 包年但未患癌症的重度吸烟者（“高度耐药”，HR）？这强烈表明存在遗传因素。将使用极端不一致表型（EDP）方法来研究这两个极端。现在可以对人类 CYP1B1 和 AHR 基因的单倍型进行系统搜索（SNP 发现，然后进行 SNP 分型）；我们已经完成了 CYP1A1_1A2 位点 (39.6 kb) 的研究，发现了 85 个 SNP，其中 49 个尚未出现在任何数据库中。我们的假设是：涉及导致高 CYP1B1 和低 CYP1A1/1A2 活性的这四种基因中的一种或多种的特定单倍型与吸烟者患 HNSCC 癌症的风险增加相关。因此，在本拟议项目的 3 年中，我们将： [a] 从六个地理上孤立的主要亚组中开展仍需要完成的任何 SNP 发现和 SNP 分型；我们将从队列中的 200 名 HS HNSCC 患者和 200 名 HR 非癌症重度吸烟者中采集血液并制备 DMA； [b] 通过对 200 名 HS 与 200 名 HR 个体的 CYP1B1、CYP1A1、CYP1A2 和 AHR 基因进行 SNP 分型，检查单倍型与 HNSCC 风险之间的关联。在 HNSCC 和这四种基因之间建立重要的表型-基因型关联将提供第一个明确的数据，表明人类在癌症和这些基因中的一个或多个方面与实验动物相似。