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

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中存在的无数多环芳烃（PAHs），亚硝胺和A/-杂环化合物，包括香烟烟雾。PAH诱导的CYP1B1/1A1/1A2基因被芳香烃受体（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高亲和力与多环芳烃引起的遗传毒性增加有关；然而，最近对基因敲除小鼠的研究表明，尽管高CYP1B1活性导致代谢激活，但CYP1A1和CYP1A2在解毒中的作用远比代谢激活重要。人类的数据还没有定论，也许是因为许多人认为所有三种CYP1酶只会导致更高的癌症风险。我们有一个大的队列头颈鳞状细胞癌（HNSCC）患者，有1到40包年的卷烟史（“高度敏感”，HS）和烟瘾大的吸烟者，有80包年没有癌症（“高度耐药”，HR）。强烈暗示有遗传成分。这两个极端将被研究，使用极端不协调表型（EDP）方法。对人类、CYP1B1和AHR基因的单倍型进行系统搜索（SNP发现后进行SNP分型）现在是可能的；我们已经完成了对CYP1A1_1A2位点（39.6 kb）的研究，发现了85个snp，其中49个尚未在任何数据库中找到。我们的假设是：涉及这四种基因中的一种或多种导致高CYP1B1和低CYP1A1/1A2活性的特定单倍型与吸烟者HNSCC癌风险增加有关。因此，在这个项目的3年里，我们将：[a]从六个主要的地理上孤立的亚群中进行任何仍需要做的snp发现和snp分型；我们将在我们的队列中收集200名HS HNSCC患者和200名HR非癌症重度吸烟者的血液并准备DMA；[b]通过对200名HS个体与200名HR个体的CYP1B1、CYP1A1、CYP1A2和AHR基因进行snp分型，检验单倍型与HNSCC风险之间的关系。在HNSCC和这四个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。

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.