Project 4 - Oral Cell DNA Adducts and Urinary Biomarkers to Investigate Ethnic/Racial Differences in Lung Cancer Susceptibility

项目 4 - 利用口腔细胞 DNA 加合物和尿液生物标志物研究肺癌易感性的民族/种族差异

基本信息

批准号：
9355615
负责人：
STEPHEN S HECHT
金额：
$ 19.1万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9355615
关键词：
1,3-Butadiene 2-butenal Acetylcysteine Acrolein Affect African American Aldehydes Alkylating Agents Aromatic Polycyclic Hydrocarbons Benzene Biological Markers Carcinogen exposure Carcinogenesis Mechanism Carcinogens Cells Cigarette Collaborations DNA DNA Adduction DNA Adducts DNA Damage DNA Modification Process DNA Repair Data Dinoprostone Dose Drug Metabolic Detoxication Ethnic group F2-Isoprostanes Formaldehyde Generations Genes Genetic Individual Inflammation Japanese American Lead Link Lung Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Measurement Measures Metabolic Activation Methods Mutation Native Hawaiian Nicotine Nitrosamines One-Step dentin bonding system Oral Oral mucous membrane structure Predisposition Prevention strategy Process Recruitment Activity Resolution Risk Sampling Smoker Smoking Technology Testing Time Tobacco Urine adduct base cancer risk carcinogenicity caucasian American cigarette smoking clinical biomarkers cohort ethnic difference high risk innovation insight lung cancer prevention never smoker non-smoker oxidative damage racial and ethnic racial difference toxicant urinary

项目摘要

Project 4. Oral Cell DNA Adducts and Urinary Biomarkers to Investigate Ethnic/Racial Differences in Lung Cancer Susceptibility. ABSTRACT Our ongoing studies demonstrate that carcinogen and toxicant doses account for some of the ethnic differences in risk for lung cancer among smokers as observed in the Multiethnic Cohort. Carcinogen and toxicant dose are only the first part of the risk paradigm for smoking-related lung cancer. DNA adduct formation is the next critical step because DNA adducts lead to the multiple mutations that are found in smokers' lungs and that cause miscoding, genetic instability, and cancer. Therefore, in this study, we will compare DNA adduct formation in smokers from three ethnic groups with differing risks for lung cancer: Native Hawaiians (highest risk), Whites (lower risk), and Japanese Americans (lowest risk). Three-hundred subjects will be recruited by the Clinical and Biomarker Core. Oral cells, as a surrogate for lung cells, will be obtained for DNA adduct measurements; urine samples will be collected for analysis of carcinogen and toxicant metabolites. Specific DNA adducts as well as DNA adductomic signatures will be obtained from oral cells of each subject. Analysis of the urine samples as well as those previously collected from never smokers will test the hypothesis that the high lung cancer susceptibility of Native Hawaiians is partially due to endogenous generation of the toxicants acrolein and crotonaldehyde, possibly due to inflammation and oxidative damage. Thus, our specific aims are: 1. Using high resolution mass spectrometry, quantify known DNA adducts in oral mucosa cells of 100 smokers from each ethnic group – Native Hawaiians, Whites, and Japanese Americans. DNA adducts of tobacco-specific compounds, formaldehyde, and acrolein will be quantified. 2. Analyze the urine of 100 smokers and 100 non-smokers from each of these groups for mercapturic acids of acrolein and crotonaldehyde, the F2-isoprostane 8-iso-PGF-2α, a biomarker of oxidative damage, and the prostaglandin E2 metabolite PGEM, a biomarker of inflammation, as well as total nicotine equivalents and total NNAL (smokers only). These data will provide critical information relevant to the high risk of Native Hawaiians for lung cancer, and in relationship to the DNA adduct measurements of Specific Aim 1. 3. Use our newly developed high resolution mass spectrometric, high throughput DNA adductomic approach to screen for known and unknown DNA adducts to identify a comprehensive DNA modification signature derived from cigarette smoking. a. Using a targeted DNA adductomic method we will screen for multiple DNA modifications simultaneously. The adducts analyzed in Specific Aim 1 will be added to a list including endogenous, 1,3-butadiene-derived (in collaboration with Project 3), aldehyde-derived and nitrosamine or alkylating agent-derived DNA adducts. In parallel we will apply our DNA adductomic method in an untargeted mode to investigate the presence of previously unknown DNA adducts. The unknown adducts detected by the untargeted analysis will be included in the list of targeted DNA adducts to ultimately obtain a sensitive method to assess overall DNA damage resulting from cigarette smoking . b. The list of DNA adducts created in Specific Aim 3a will be applied to investigate differences in the DNA damage signature in selected samples analyzed in Specific Aim 1. The results of this unique and innovative study will provide critical information relevant to the differing risks for lung cancer among Native Hawaiians, Whites, and Japanese Americans. We expect generation of new smoking-related DNA adduct signatures as well as important data on DNA adducts and urinary metabolites of known carcinogens and toxicants. The results will provide a critical test of the relationship of DNA adducts and certain urinary metabolites to lung cancer risk, thus possibly leading to new insights for lung cancer prevention strategies.

项目 4. 口腔细胞 DNA 加合物和尿液生物标志物研究民族/种族差异肺癌易感性。抽象的我们正在进行的研究表明，致癌物和有毒物质剂量对某些种族有影响在多种族致癌物和吸烟者中观察到的肺癌风险差异。毒物剂量只是吸烟相关肺癌 DNA 加合物形成风险范例的第一部分。是下一个关键步骤，因为 DNA 加合物会导致吸烟者肺部中发现的多种突变因此，在这项研究中，我们将比较 DNA 加合物。来自三个种族的吸烟者患肺癌的风险不同：夏威夷原住民（最高）将招募三百名受试者将获得作为肺细胞替代物的临床和生物标记核心。测量；收集尿液样本以分析致癌物和特定有毒代谢物。 DNA 加合物以及 DNA 加合物特征将从每个受试者的口腔细胞中获得。尿液样本以及之前从不吸烟者身上收集的尿液样本将检验以下假设：夏威夷原住民肺癌易感性高的部分原因是内源性有毒物质的产生丙烯醛和巴豆醛，可能是由于炎症和氧化损伤。因此，我们的具体目标是： 1. 使用高分辨率质谱法，对 100 个口腔粘膜细胞中已知的 DNA 加合物进行定量来自各个民族的吸烟者——夏威夷原住民、白人和日裔美国人的 DNA 加合物。烟草特有的化合物、甲醛和丙烯醛将被量化。 2. 分析每组 100 名吸烟者和 100 名非吸烟者的尿液中的硫醇酸丙烯醛和巴豆醛、F2-异前列腺素 8-iso-PGF-2α（氧化损伤的生物标志物）以及前列腺素 E2 代谢物 PGEM（炎症生物标志物）以及总尼古丁当量和总 NNAL（仅限吸烟者）。这些数据将提供与 Native 高风险相关的关键信息。夏威夷人肺癌，以及与特定目标 1 的 DNA 加合物测量的关系。 3. 使用我们新开发的高分辨率质谱、高通量 DNA 加合体方法筛选已知和未知的 DNA 加合物，以确定全面的 DNA 修饰特征源自吸烟。 a. 使用靶向 DNA 加合方法，我们将筛选多种 DNA 修饰同时，特定目标 1 中分析的加合物将添加到包含在内的列表中。内源性、1,3-丁二烯衍生（与项目 3 合作）、醛衍生和同时，我们将应用我们的 DNA 加合物。方法以非靶向模式研究先前未知的 DNA 加合物的存在。非目标分析检测到的未知加合物将包含在目标列表中 DNA 加合物最终获得一种灵敏的方法来评估由 DNA 引起的整体 DNA 损伤吸烟。 b. 在特定目标 3a 中创建的 DNA 加合物列表将用于研究具体目标 1 中分析的选定样品中的 DNA 损伤特征。这项独特且创新的研究结果将提供与不同风险相关的关键信息。我们预计新一代夏威夷人、白人和日裔美国人会罹患肺癌。与吸烟相关的 DNA 加合物特征以及 DNA 加合物和尿代谢物的重要数据已知的致癌物和毒物的结果将为 DNA 加合物和毒物之间的关系提供关键测试。某些尿液代谢物会增加肺癌风险，从而可能为肺癌预防带来新的见解策略。