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

描述（由申请人提供）：本提案汇集了在烟草致癌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裔美国人。我们假设，这些肺癌易感性的差异是由于暴露和对香烟烟雾致癌物的反应的民族和种族差异。这一假设将通过独特的基因、生物标志物和机制研究的组合来检验，这些研究将使用创新的技术，并依靠精湛的国际公认的专业知识。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摄取和代谢激活的表型生物标志物之间的关系。将对五个民族/种族群体（每组450名受试者）进行全基因组关联研究，并将研究结果与烟草烟雾成分尼古丁和致癌物生物标志物的研究结果相结合。高度整合的项目2-5将与项目1合作，并利用项目负责人的精湛专业知识研究相关机制。项目2，“吸烟者的尼古丁和NNK糖醛酸化途径”，将研究尼古丁和烟草特异性肺癌物质4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）代谢的种族差异，重点研究至关重要的糖醛酸化解毒途径。项目3，“1,3-丁二烯代谢和DNA加合物形成的种族差异”，将重点关注1,3-丁二烯代谢的种族差异。项目4，“DNA修复中的种族差异”，将研究DNA修复在防止香烟致癌物质的致突变性和致癌性方面的关键作用。项目5“非裔美国人的NNK代谢”将直接检验烟草特异性肺癌物质NNK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。该项目独特的专业知识组合形成了一个强大的团队，在研究不同种族/种族吸烟者肺癌发展机制的能力方面可以说是无与伦比的。

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.