Project 1 - Ethnic Differences in Smoking-Related Biomarkers and Risk of Lung Cancer

摘要 在世界范围内，肺癌是最常见的癌症，也是癌症相关死亡的主要原因。同时， 吸烟是这种疾病的主要危险因素，只有15-20%的吸烟者会患上肺癌。 此外，我们在多种族队列（MEC）研究中表明，平均而言，对于相同数量的 与白人相比，非裔美国人和夏威夷原住民吸烟的风险高出50%。 发展肺癌;而日裔美国人和拉丁美洲人患肺癌的风险降低25%。在 在前一个资助期，我们发现，内部吸烟剂量，如尿总尼古丁当量测量， (TNE)在非裔美国人中最高，日裔美国人较低。这与他们的 人群肺癌风险。然而，在夏威夷土著人和拉丁美洲人中， 剂量和烟草毒物暴露和代谢，只有丙烯醛和巴豆醛的生物标志物 与肺癌风险的方向性相关。我们初步的DNA甲基化数据表明， 剂量可能会影响不同种族/民族的表观基因组。此外，我们的初步 MEC中的分析表明，体内吸烟剂量随时间（TNE-年）和尼古丁的生物标志物 代谢（细胞色素P450 2A 6活性）与肺癌风险增加相关，即使在 调整自我报告的吸烟剂量（包-年）。拟议研究的目的是 确定与吸烟相关的肺癌风险相关的生物标志物， 了解肺癌风险中种族/种族差异的潜在机制。我们建议 进行一项表观基因组范围内的血液白细胞DNA甲基化与吸烟剂量的关联研究， 烟草毒物暴露和代谢的生物标志物（目的1）。我们还将系统地调查 烟草毒物暴露和代谢的生物标志物的关联（n= 1，865例病例和3，619例对照） 和血液白细胞中的DNA甲基化（n= 1，600例病例和3，354例对照）与肺癌风险（目的2）。 此外，在其他项目中鉴定的任何生物标志物（例如，项目3和4：1，3-二氢呋喃的尿DNA加合物）也可用于检测尿中的DNA。 丁二烯、丙烯醛和巴豆醛），这表明有希望解释疾病风险的差异 还将评估与肺癌风险的潜在关联。我们假设种族/种族和 肺癌风险的个体差异是由于对普通烟草肺的不同生物反应 有毒物质，这将反映在吸烟剂量，烟草毒物暴露和 代谢和DNA甲基化图谱。这项研究的发现将扩大我们对 吸烟相关的肺癌机制和肺癌风险的种族/种族差异。的 识别风险生物标志物将有助于开发新的戒烟干预措施， 在高危人群中开展有针对性的肺癌筛查工作。

ABSTRACT Worldwide, lung cancer is the most common cancer and the leading cause of cancer-related deaths. While, cigarette smoking is the primary risk factor for this disease, only 15-20% of smokers will develop lung cancer. Moreover, we showed in the Multiethnic Cohort (MEC) Study that, on the average and for the same quantity of cigarette smoke, compared to whites, African Americans and Native Hawaiians have a 50% greater risk of developing lung cancer; whereas, Japanese Americans and Latinos have a 25% lower risk of the disease. In the prior funding period, we found that internal smoking dose, as measured by urinary total nicotine equivalents (TNE), was highest in African Americans and lower in Japanese Americans. This correlates with their population lung cancer risks. However, in Native Hawaiians and Latinos among biomarkers of internal smoking dose and tobacco toxicant exposure and metabolism, only the biomarkers for acrolein and crotoaldehyde correlated with directionality of lung cancer risk. Our preliminary DNA methylation data suggests that smoking dose may influence the epigenome differentially across racial/ethnic groups. Additionally, our preliminary analysis in MEC suggested that biomarkers of internal smoking dose over time (TNE-years) and of nicotine metabolism (cytochrome P450 2A6 activity) are associated with an increased risk of lung cancer, even after adjusting for self-reported measures of smoking dose (pack-years). The objectives of the proposed study are to identify biomarkers that are associated with smoking-related lung cancer risk and to improve our understanding of the mechanisms underlying the ethnic/racial differences in lung cancer risk. We propose to conduct an epigenome-wide association study of blood leukocyte DNA methylation with smoking dose and biomarkers of tobacco toxicant exposure and metabolism (Aim 1). We will also systematically investigate the association of biomarkers of tobacco toxicant exposure and metabolism (n=1,865 cases and 3,619 controls) and DNA methylation in blood leukocytes (n=1,600 cases and 3,354 controls) with lung cancer risk (Aim 2). Additionally, any biomarkers identified in the other projects (e.g. Projects 3 and 4: urinary DNA adducts of 1,3- butadiene, acrolein, and crotoaldehyde) that show a promise towards explaining the difference in disease risk will also be evaluated for potential associations with risk of lung cancer. We hypothesize that ethnic/racial and individual differences in lung cancer risk are due to disparate biological response to common tobacco lung toxicants, which will be reflected by variations in biomarkers of smoking dose, tobacco toxicant exposure and metabolism, and DNA methylation profiles. The findings from this study will expand our understanding of the smoking-related mechanisms of lung cancer and the ethnic/racial differences in lung cancer risk. The identification of risk biomarkers will aid in the development of novel smoking cessation interventions and targeted lung cancer screening efforts in high risk populations.