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

摘要 该计划项目资助具有高度整合的科学家团队，具有不同的相关专业知识， 确定所观察到的吸烟对肺癌易感性的种族差异的机制基础 吸烟者。他们的研究是基于多种族队列研究的一个主要线索，该研究表明， 对于相同数量的吸烟，特别是在吸烟水平较低的情况下， 美国人和夏威夷原住民的肺癌发病率高于白人，而拉丁裔和 日裔美国人的发病率较低。他们将在前五年取得的重要成果的基础上再接再厉 证明尼古丁代谢和致癌物摄取存在显著差异， 部分解释了非洲裔美国人相对高的风险和日裔美国人的低风险。四 项目将利用他们在流行病学，遗传学，表观遗传学，生物统计学，分析化学， 生物化学和烟草致癌作用。项目1，吸烟相关生物标志物的种族差异， 肺癌的风险，将评估DNA甲基化谱是否在种族/民族之间存在差异， 研究全基因组DNA甲基化与吸烟剂量生物标志物之间的关系， 尼古丁代谢、烟草致癌物和毒物生物标志物以及DNA甲基化与肺的关系 吸烟者的癌症项目2，4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）α-羟基 葡萄糖醛酸苷、代谢特征和活化将确定CYP 2A 6基因型对NNK的影响 在具有不同CYP 2A 6活性的日裔美国吸烟者中进行代谢活化，并使用独特的氘代 NNK代谢谱分析方法用于表征这些患有不同肺癌的群体中的NNK代谢 风险项目3，1，3-丁二醇代谢和DNA加合物形成的种族/种族差异，将 调查不同种族吸烟者尿液中丁二烯-DNA加合物的种族差异 探讨DNA加合物与肺癌的关系及对致癌物代谢的影响 基因对DNA加合物形成、修复和毒性/致突变性的影响。项目4，口腔细胞DNA加合物和 研究肺癌易感性种族/种族差异的尿液生物标志物将量化已知的 夏威夷土著人、白色人和日裔美国人口腔粘膜细胞中以前未知的DNA加合物 吸烟者，并将研究尿中丙烯醛，巴豆醛，炎症和氧化 吸烟者和非吸烟者之间的损害。这些项目得到三个 具有独特世界级专业知识的卓越核心：核心A，管理;核心B，临床和生物标志物;以及 核心C，生物统计学。总之，我们提出了一个独特的多学科方法来研究机制， 肺癌易感性的种族/种族差异。我们希望继续产生声音，令人兴奋， 相关的多学科机制数据，为肺癌预防带来新的见解。 本案无关肺癌是世界上癌症死亡的主要原因， 2012.在美国，大约90%的肺癌发病率和死亡率是由于吸烟。我们 预防肺癌的方法是基于对烟草诱发癌症的机制的理解， 这将为预防带来新的见解。该计划项目赠款调查这些机制使用 建立了种族/种族易感性的差异作为基础。

ABSTRACT This program project grant features a highly integrated team of scientists with diverse relevant expertise to determine the mechanistic basis for the observed ethnic differences in susceptibility to lung cancer in cigarette smokers. Their studies are based on a major lead form the Multiethnic Cohort study which demonstrated that, for the same number of cigarettes smoked, and particularly at lower levels of smoking, self-identified African Americans and Native Hawaiians have a higher incidence of lung cancer than Whites while Latinos and Japanese Americans have a lower incidence. They will build on their important results from the first five years of this project demonstrating significant differences in nicotine metabolism and carcinogen uptake which partially explain the relatively high risk of African Americans and the low risk of Japanese Americans. Four projects will draw on their expertise in epidemiology, genetics, epigenetics, biostatistics, analytical chemistry, biochemistry, and tobacco carcinogenesis. Project 1, Ethnic Differences in Smoking-Related Biomarkers and Risk of Lung Cancer, will evaluate whether DNA methylation profiles differ across racial/ethnic groups, investigate the relationship between genome-wide DNA methylation and biomarkers of smoking dose, and the relationship of nicotine metabolism, tobacco carcinogen and toxicant biomarkers, and DNA methylation to lung cancer in current smokers. Project 2, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) α-Hydroxy Glucuronides, Metabolic Profiling and Activation, will determine the effect of CYP2A6 genotype on NNK metabolic activation in Japanese American smokers with differing CYP2A6 activity, and use unique deuterated NNK metabolic profiling methods to characterize NNK metabolism in these groups with diverse lung cancer risk. Project 3, Ethnic/racial Differences in Metabolism and DNA Adduct Formation by 1,3-Butadiene, will investigate ethnic differences in butadiene-DNA adducts in the urine of smokers from different ethnic groups and determine the relationship of DNA adducts to lung cancer and the influence of carcinogen metabolizing genes on DNA adduct formation, repair, and toxicity/mutagenicity. Project 4, Oral Cell DNA Adducts and Urinary Biomarkers to Investigate Ethnic/Racial Differences in Lung Cancer Susceptibility, will quantify known and previously unknown DNA adducts in oral mucosa cells of Native Hawaiian, White, and Japanese American smokers and will investigate urinary biomarkers of acrolein, crotonaldehyde, inflammation, and oxidative damage among smokers and non-smokers from these ethnic groups. These projects are supported by three superb cores with unique world class expertise: Core A, Administrative; Core B, Clinical and Biomarkers; and Core C, Biostatistics. In summary, we present a unique multidisciplinary approach to study mechanisms of ethnic/racial differences in lung cancer susceptibility. We expect to continue to generate sound, exciting, and relevant multidisciplinary mechanistic data leading to new insights for lung cancer prevention. RELEVANCE. Lung cancer is the leading cause of cancer death in the world, causing 1,589,800 deaths in 2012. Approximately 90% of lung cancer incidence and mortality in the U.S. is due to cigarette smoking. Our approach to lung cancer prevention is based on an understanding of mechanisms of tobacco-induced cancer, which will lead to new insights for prevention. This program project grant investigates these mechanisms using established differences in ethnic/racial susceptibility as a base.