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

人类 HNSCC：CYP1B1/1A1/1A2 和 AHR 基因多态性

基本信息

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
项目类别：
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

项目摘要

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.

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. PAH-诱导的CYP1B1/1A1/1A2基因被芳香族烃受体（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PAHS引起的遗传毒性增加相关。然而，最近对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在排毒中比代谢激活更为重要。人类的数据尚无定论，也许是因为许多人都假设所有三种CYP1酶仅会导致更高的癌症风险。我们有大量的头颈鳞状细胞癌（HNSCC）患者，病史为1至40次香烟包装年（“高度敏感”，HS）和> 80个包装年度的沉重吸烟者（“高度抗性”（“高度抗性”，HR）？强烈暗示一个遗传成分。使用极端不一致的表型（EDP）方法，将研究这两个极端。对于人类的单倍型，CYP1B1和AHR基因现在是可能的。我们已经完成了对CYP1A1_1A2基因座（39.6 KB）的研究，并发现了85个SNP，其中49个尚未在任何数据库中。我们的假设是：涉及这四个基因中的一个或多个导致CYP1B1高和CYP1A1/1A2活性低的特定单倍型与吸烟者中HNSCC癌的风险增加有关。因此，在这个提议的项目的三年中，我们将：[a]从六个主要地理位置隔离的亚组中执行仍然需要完成的SNP划分和SNP型；我们将收集血液，并在我们的队列中从200个HS HNSCC患者和200个小时的非癌症吸烟者中准备DMA； [b]通过对200 HS与200 HR个体进行CYP1B1，CYP1A1，CYP1A2和AHR基因的SNP型，检查单倍型与HNSCC风险之间的关联。建立HNSCC与这四个基因之间的重要表型基因型关联将提供第一个明确的数据，即人类与实验动物有关癌症和其中一个或多个这些基因的数据相似。