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

项目 1 - 吸烟相关生物标志物的种族差异和肺癌风险

基本信息

批准号：
9149448
负责人：
Sungshim Lani Park
金额：
$ 53.33万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2021-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9149448
关键词：
1,3-Butadiene 2-butenal Accounting Acrolein Affect African American Age Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Benzene Biological Biological Markers Blood Cancer Etiology Carcinogens Categories Cessation of life Cigarette Cohort Studies Cotinine Cytochrome P450 DNA DNA Adducts DNA Methylation Data Development Disease Dose Epigenetic Process Ethnic Origin Ethnic group Exposure to Funding Genes Hawaiian population Individual Differences Inflammation Investigation Japanese American Joints Latino Lead Leukocytes Lung Malignant Neoplasms Malignant neoplasm of lung Measures Metabolic Metabolism Metals Methods Methylation Nested Case-Control Study Nicotine Oxidative Stress Participant Pathway interactions Patient Self-Report Plasma Population Race Reporting Risk Risk Factors Sampling Smoke Smoker Smoking Smoking Cessation Intervention Smoking History Testing Time Tobacco Tobacco-Associated Carcinogen Toxicant exposure Urine Variant base bead chip cancer risk case control cigarette smoking cigarette smoking cohort disorder risk epigenome epigenome-wide association studies ethnic difference genome-wide high risk improved lung cancer prevention lung cancer screening methylation biomarker novel predictive modeling racial and ethnic racial difference response sex smoking cessation toxicant uptake urinary

项目摘要

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.

抽象的在世界范围内，肺癌是最常见的癌症，也是癌症相关死亡的主要原因。尽管，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% 罹患肺癌；而日裔美国人和拉丁美洲人患这种疾病的风险要低 25%。在在之前的资助期间，我们发现内部吸烟剂量（通过尿液总尼古丁当量测量） (TNE)，在非裔美国人中最高，在日裔美国人中较低。这与他们的人群患肺癌的风险。然而，在夏威夷原住民和拉丁美洲人中，内部吸烟的生物标志物剂量与烟草毒物暴露和代谢有关，仅生物标志物为丙烯醛和巴豆醛与肺癌风险的方向性相关。我们的初步 DNA 甲基化数据表明吸烟剂量可能对不同种族/族裔群体的表观基因组产生不同的影响。此外，我们初步 MEC 的分析表明，体内吸烟剂量随时间变化（TNE 年）和尼古丁的生物标志物代谢（细胞色素 P450 2A6 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测量值（包年）。拟议研究的目标是识别与吸烟相关的肺癌风险相关的生物标志物，并改善我们的了解肺癌风险中民族/种族差异的潜在机制。我们建议进行血液白细胞 DNA 甲基化与吸烟剂量的全表观基因组关联研究烟草毒物暴露和代谢的生物标志物（目标 1）。我们还将系统地调查烟草毒物暴露和代谢生物标志物的关联（n=1,865 例病例和 3,619 例对照）血液白细胞中的 DNA 甲基化（n=1,600 例病例和 3,354 名对照）与肺癌风险相关（目标 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- 尿 DNA 加合物）丁二烯、丙烯醛和巴豆醛）有望解释疾病风险的差异还将评估与肺癌风险的潜在关联。我们假设民族/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造成的有毒物质，这将通过吸烟剂量、烟草毒物暴露和烟草毒物暴露的生物标志物的变化来反映代谢和 DNA 甲基化谱。这项研究的结果将扩大我们对吸烟相关的肺癌机制以及肺癌风险的民族/种族差异。这风险生物标志物的识别将有助于开发新型戒烟干预措施对高危人群开展有针对性的肺癌筛查工作。