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

摘要 肺癌是美国癌症死亡的主要原因。此续订申请为期11-15年 题为“吸烟导致肺癌的民族/种族差异的机制”的项目资助 吸烟“汇聚了我们在癌症分子流行病学、烟草控制、 烟草致癌的机制和生物化学，以及继续我们突破性进展的生物统计学 吸烟致肺的生化、分子和表观遗传学机制研究 癌症。我们将以正在进行的研究的重要发现为基础，这些研究包括在 肺癌的表观遗传学、尼古丁导致成瘾和癌症的生物化学、烟草对DNA的损伤 吸烟致癌物质包括丙烯醛和1，3-丁二烯，以及烟草致癌生物标志物研究 阐述和解释来自5个种族的吸烟者之间肺癌发病率的显著差异 群体--非洲裔美国人、夏威夷原住民、白人、拉丁裔和日裔美国人。项目1，“基因 和曾吸烟者患肺癌的表观遗传风险标记物“建议识别这些肺部标记物 戒烟者的癌症风险，并提高了我们对 曾吸烟者患肺癌的风险。项目2，“CYP2A6基因评分、尼古丁代谢和肺 癌症“将重点放在尼古丁代谢的主要催化剂上，这是至关重要的，因为 这种酶的活性减少了吸烟的次数，减少了吸烟的强度，因为它们需要的香烟更少。 尼古丁，它被认为可以降低患肺癌的风险。项目3，“非定向内收摘除 描述吸烟者暴露的种族差异“假设生物对 由于遗传和/或表观遗传因素，个人和种族之间的香烟烟雾暴露有所不同 这会导致对吸烟的新陈代谢和炎症反应的差异。项目4，“致癌” 多种族队列研究的前吸烟者中的生物标记物将使用一种独特的方法来确定 多环芳烃在大鼠肺内的代谢活化及脂质过氧化 吸烟者与从不吸烟者相比。这4个项目将得到3个突出核心的支持： 管理核心，临床和生物标志物核心，以及生物统计学核心。因此，我们经验丰富的调查人员 建议继续他们精湛而独特的团队合作，以在了解肺方面取得重大进展 现吸烟者和曾经吸烟者的致癌机制为预防吸烟提供了新的见解 致命的肺癌。

ABSTRACT Lung cancer is the leading cause of cancer death in the U.S. This renewal application for years 11-15 of our Program Project Grant entitled “Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking” brings together our team of renowned experts in cancer molecular epidemiology, tobacco control, mechanisms and biochemistry of tobacco carcinogenesis, and biostatistics to continue our groundbreaking research on biochemical, molecular, and epigenetic mechanisms by which cigarette smoking causes lung cancer. We will build on our significant findings from ongoing studies which include important advances in the epigenetics of lung cancer, biochemistry of nicotine leading to addiction and cancer, DNA damage by tobacco smoke carcinogens including acrolein and 1,3-butadiene, and tobacco carcinogen biomarker studies which expand and explain the dramatic differences in lung cancer incidence among cigarette smokers from 5 ethnic groups – African Americans, Native Hawaiians, Whites, Latinos, and Japanese Americans. Project 1, “Genetic and epigenetic risk markers for lung cancer in former smokers” proposes to identify these markers of lung cancer risk in people who have quit smoking and improve our understanding of the ethnic/racial differences in lung cancer risk among former smokers. Project 2, “CYP2A6 genetic score, nicotine metabolism, and lung cancer” will focus on the primary catalyst of nicotine metabolism which is critical because people with low activity of this enzyme smoke fewer cigarettes and smoke those less intensely because they need less nicotine, which is proposed to lead to lower lung cancer risk. Project 3, “Untargeted adductomics to characterize ethnic differences in the exposome of smokers” hypothesizes that biological responses towards cigarette smoke exposure differ among individuals and ethnic groups due to genetic and/or epigenetic factors that lead to differences in metabolic and inflammatory responses to smoking. Project 4, “Carcinogenesis biomarkers in former smokers of the Multiethnic Cohort Study” will use a unique approach to determine the metabolic activation of polycyclic aromatic hydrocarbons as well as lipid peroxidation in the lungs of former smokers compared to never smokers. These 4 projects will be supported by 3 outstanding Cores: Administrative Core, Clinical and Biomarkers Core, and Biostatistics Core. Thus, our experienced investigators propose to continue their superb and unique teamwork to make significant progress in understanding lung cancer mechanisms among present and former cigarette smokers leading to new insights for prevention of fatal lung cancer.