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: 7765754
• 负责人: STEPHEN S HECHT
• 金额: $ 195.15万
• 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/7765754
• 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癌变和基因组广泛关联研究方面具有丰富专业知识的研究人员，以研究由于吸烟而引起的肺癌中的种族/种族差异。在吸烟者中，非裔美国人和夏威夷人的风险更高，而日裔美国人和拉丁美洲人患肺癌的风险低于欧洲美国人。我们假设肺癌易感性的这些差异是由于种族和种族差异引起的暴露和对香烟烟雾致癌的反应。该假设将通过使用创新技术的遗传，生物标志物和机械研究的独特组合进行检验，并依靠出色的国际公认的专业知识。如果支持这一假设，我们对烟草诱导的肺癌的机械理解将大大增加，从而为预防肺癌提供重要的新见解。项目1，“代谢表型的多种族基因组扫描”将检查常见遗传变异与不同种族/种族群体中烟草烟雾组成摄取和代谢激活的表型生物标志物的关联。将对五个族裔/种族群体（每组450名受试者）进行一项基因组广泛的研究，并将结果与​​烟碱和致癌物的烟草烟雾组成生物标志物的结果整合在一起。高度集成的项目2-5将与项目1合作，并利用项目负责人的出色专业知识来研究相关机制。项目2，“吸烟者中的尼克丁和NNK葡萄糖醛酸化途径”，将研究尼古丁代谢和烟草特异性肺癌4-（甲基硝基氨基）-1-（3-吡啶基）-1-1-叔丁酮（NNK）的种族差异，重点介绍crucial glucuronidation。项目3，“ 1,3-丁二烯代谢和DNA加合物形成的种族/种族差异”将重点关注1,3-丁二烯代谢的种族和种族差异。项目4，“ DNA修复中的种族/种族差异”，将研究DNA修复在防止香烟烟雾致癌性诱变和致癌性中的关键作用。项目5，“非裔美国人中NNK的代谢”将直接检验以下假设：烟草特异性肺癌的代谢存在种族和种族差异。这些项目将得到三个核心的支持：A，行政； B，烟草烟雾组成生物标志物；和C，生物统计学。该计划项目中专业知识的独特组合构成了一个强大的团队，可以说是解决来自不同种族/种族群体吸烟者肺癌开发机制的能力。