Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking

吸烟导致肺癌的民族/种族差异机制

• 批准号: 8055021
• 负责人: STEPHEN S HECHT
• 金额: $ 197.51万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055021
• 关键词: Mechanisms; Ethnic; Racial; Differences; Lung

DESCRIPTION (provided by applicant): This proposal brings together investigators with great expertise in tobacco carcinogenesis and genome wide association studies to investigate ethnic/ racial differences in lung cancer due to cigarette smoking. Among cigarette smokers, African Americans and Native Hawaiians have a higher risk, while Japanese Americans and Latinos have a lower risk for lung cancer than European Americans. We hypothesize that these differences in lung cancer susceptibility are due to ethnic and racial variations in exposure and response to cigarette smoke carcinogens. This hypothesis will be tested through a unique combination of genetic, biomarker, and mechanistic studies using innovative techniques and relying on superb internationally recognized expertise. If this hypothesis is supported, our mechanistic understanding of tobacco-induced lung cancer will increase immensely, thus providing important new insights for lung cancer prevention. Project 1, "Multiethnic Genome Scan of Metabolic Phenotypes" will examine the association of common genetic variants with phenotypic biomarkers of tobacco smoke constituent uptake and metabolic activation in different ethnic/racial groups. A genome wide association study of five ethnic/racial groups (450 subjects per group) will be carried out and the results integrated with those of tobacco smoke constituent biomarkers for nicotine and carcinogens. The highly integrated Projects 2-5 will collaborate with Project 1 and use the superb expertise of the project leaders to study the relevant mechanisms. Project 2, "Nicotine and NNK Glucuronidation Pathways in Smokers," will investigate ethnic differences in the metabolism of nicotine and the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), focusing on the crucial glucuronidation detoxification pathway. Project 3, "Ethnic/Racial Differences in 1,3-Butadiene Metabolism and DNA Adduct Formation," will focus on ethnic and racial differences in the metabolism of 1,3- butadiene. Project 4, "Ethnic/Racial Differences in DNA Repair," will investigate the critical role of DNA repair in protecting against mutagenicity and carcinogenicity of cigarette smoke carcinogens. Project 5, "Metabolism of NNK among African Americans," will directly test the hypothesis that there are ethnic and racial differences in the metabolism of the tobacco-specific lung carcinogen NNK. The projects will be supported by three Cores: A, Administrative; B, Tobacco Smoke Constituent Biomarker; and C, Biostatistics. The unique combination of expertise in this program project forms a powerful team arguably unmatched in its ability to address mechanisms of lung cancer development in smokers from different ethnic/racial groups.

描述（由申请人提供）：该提案汇集了在烟草致癌和全基因组关联研究方面拥有丰富专业知识的研究人员，以调查吸烟引起的肺癌的种族/种族差异。在吸烟者中，非裔美国人和夏威夷原住民患肺癌的风险较高，而日裔美国人和拉丁裔美国人患肺癌的风险低于欧洲裔美国人。我们假设肺癌易感性的这些差异是由于民族和种族对香烟烟雾致癌物的暴露和反应的差异造成的。这一假设将通过使用创新技术并依靠国际公认的精湛专业知识，通过遗传、生物标志物和机制研究的独特组合来检验。如果这一假设得到支持，我们对烟草诱发肺癌的机制的理解将大大增加，从而为肺癌的预防提供重要的新见解。项目 1“代谢表型的多民族基因组扫描”将研究不同民族/种族群体中常见遗传变异与烟草烟雾成分吸收和代谢激活的表型生物标志物的关联。将开展五个民族/种族群体（每组 450 名受试者）的全基因组关联研究，并将结果与​​烟草烟雾成分中尼古丁和致癌物生物标志物的结果相结合。高度集成的项目2-5将与项目1合作，利用项目负责人精湛的专业知识研究相关机制。项目 2“吸烟者的尼古丁和 NNK 葡萄糖醛酸化途径”将调查尼古丁和烟草特有的肺癌致癌物 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 代谢的种族差异，重点关注关键的葡萄糖醛酸化解毒途径。项目 3“1,3-丁二烯代谢和 DNA 加合物形成的民族/种族差异”将重点关注 1,3-丁二烯代谢的民族和种族差异。项目 4“DNA 修复中的民族/种族差异”将研究 DNA 修复在防止香烟烟雾致癌物的致突变性和致癌性方面的关键作用。项目5“非裔美国人中NNK的代谢”将直接检验烟草特异性肺癌致癌物NNK的代谢存在民族和种族差异的假设。这些项目将得到三个核心的支持：A，行政； B、烟草烟雾成分生物标志物； C，生物统计学。该计划项目中独特的专业知识组合形成了一个强大的团队，其解决不同民族/种族群体吸烟者肺癌发展机制的能力可以说是无与伦比的。