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具有丰富专业知识的研究人员，以研究吸烟导致肺癌的种族/种族差异。在吸烟者中，非裔美国人和夏威夷土著人患肺癌的风险较高，而日裔美国人和拉丁美洲人患肺癌的风险低于欧洲裔美国人。我们假设这些肺癌易感性的差异是由于种族和种族对香烟烟雾致癌物的暴露和反应的差异。这一假设将通过独特的遗传学、生物标志物和机制研究的组合进行测试，这些研究使用创新技术并依赖于国际公认的精湛专业知识。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，从而为肺癌预防提供重要的新见解。项目1，“代谢表型的多种族基因组扫描”将研究不同种族/种族群体中常见遗传变异与烟草烟雾成分摄取和代谢活化的表型生物标志物的关联。将对5个种族/人种组（每组450例受试者）进行全基因组关联研究，并将结果与尼古丁和致癌物的烟草烟雾成分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，并利用项目负责人的高超专业知识来研究相关机制。项目2，“吸烟者的尼古丁和NNK葡萄糖醛酸化途径”，将研究尼古丁和烟草特异性肺致癌物4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）代谢的种族差异，重点是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加合物形成的种族/人种差异”，将侧重于1，3-丁二烯代谢的种族和人种差异。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物的致突变性和致癌性方面的关键作用。项目5，“NNK在非裔美国人中的代谢”，将直接检验烟草特异性肺癌致癌物NNK的代谢存在种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;和C，生物统计学。该计划项目中专业知识的独特组合形成了一个强大的团队，可以说在解决来自不同种族/种族群体的吸烟者肺癌发展机制的能力方面无与伦比。