Comprehensive molecular characterization of lung cancers in five racial/ethnic groups with disparate risk

摘要 肺癌是两人第二常见的癌症，也是两人癌症相关死亡的主要原因。 以及美国所有主要种族/民族的妇女。吸烟是导致肺部疾病的最大危险因素 癌症。然而，在多种族队列研究(MEC)中，我们表明，即使考虑到吸烟 历史(数量、持续时间和戒烟率)，非裔美国人和夏威夷原住民患病风险更高 与白人相比，日裔美国人和拉丁裔的风险更低。肺癌是一种 具有四种主要组织细胞类型和种族/民族差异的异质性疾病在所有细胞中持续存在- 类型。我们已经报道了导致吸烟相关肺癌差异的机制。 风险，我们调查了生活方式和健康行为，吸烟及其致癌物的内部生物剂量， 以及吸烟对多种族人群血液白细胞DNA甲基化的影响。在……里面 最近的一项研究报告了比较非裔美国人和白人肺ADC的基因表达谱， 他们发现，与非裔美国人相比，肺ADC肿瘤在肿瘤生物学上存在差异 对白人来说，这表明种族/民族差异可能反映在潜在肺肿瘤的差异上。 生物学。然而，到目前为止，包括其他少数民族群体在内的全面分子研究还没有 已经进行过了。因此，这项提议的目标是从分子水平描述最常见的肺癌细胞类型， ADC，来自MEC的五个种族/民族，全面检查肿瘤的种族/民族差异 可能导致种族/民族差异的生物学因素。对于我们的第一个目标，我们将进行全面的 利用肺部ADC进行全基因组DNA甲基化和转录组分析种族/民族差异 750例多民族肺癌患者的肿瘤组织(非裔美国人、拉丁裔、夏威夷土著、日本人 美国人和白人)。我们将调整潜在的混杂因素，如年龄、性别、种族/民族、吸烟状况、 肿瘤分期。为了我们的第二个目标，我们将研究DNA甲基化和转录之间的联系 肺ADC肿瘤与肺ADC存活率的关系以及种族/民族的影响修正。对于第三个目标， 我们将检查DNA甲基化和转录图谱是否介导了 种族/民族和肺ADC存活率。此外，我们将整合DNA甲基化、转录、风险因素， 和死亡数据，以确定与疾病生存相关的新的肺癌亚组。它的优势在于 研究包括1)大型综合性分子研究设计，2)优质资源的利用 在MEC内部，以及3)多学科调查小组。这项研究的结果将提供信息 论种族/民族差异的生物学机制及其发展的证据基础 制定新的个人化治疗目标和战略，以减轻肺癌的种族/民族差异。

ABSTRACT Lung cancer is the second most common cancer and the leading cause of cancer-related death for both men and women for all major racial/ethnic groups in the United States. Smoking is the strongest risk factor for lung cancer. However, in the Multiethnic Cohort study (MEC), we showed that even when accounting for smoking history (quantity, duration and quit rates), African Americans and Native Hawaiians had higher risk of disease and Japanese Americans and Latinos had a lower risk when compared to whites. Lung cancer is a heterogeneous disease with four major histologic cell-types and racial/ethnic disparities persists across all cell- types. We have reported on the mechanisms contributing to these differences in smoking-related lung cancer risk, we examined lifestyle and health behaviors, internal biologic dose of tobacco smoking and its carcinogens, as well as the influence of smoking on DNA methylation of blood leukocytes across a multiethnic population. In a recent study reporting on gene expression profiles to compare lung ADC from African Americans and whites, they found that there were differences in tumor biology for lung ADC tumors from African Americans compared to whites, suggesting that racial/ethnic disparities may be reflected in differences in the underlying lung tumor biology. However, to date, a comprehensive molecular study that includes other minority populations has not yet been conducted. Thus, the goal of this proposal is to molecularly profile the most common lung cancer cell-type, ADC, from five racial/ethnic groups in the MEC to comprehensively examine for racial/ethnic differences in tumor biology that may be contributing to the racial/ethnic disparities. For our first aim, we will conduct a comprehensive genome-wide DNA methylation and transcriptome analysis for differences by race/ethnicity using lung ADC tumor tissue from 750 multiethnic lung cancer cases (African Americans, Latinos, Native Hawaiians, Japanese Americans, and whites). We will adjust for potential confounders such as age, sex, race/ethnicity, smoking status, and tumor stage. For our second aim, we will examine the association for DNA methylation and transcriptomic profiles of lung ADC tumors with lung ADC survival and effect modification by race/ethnicity. For the third aim, we will examine whether DNA methylation and transcriptomic profiles mediate the association between race/ethnicity and lung ADC survival. In addition, we will integrate DNA methylation, transcriptomic, risk factor, and death data to identify novel lung cancer subgroups associated with disease survival. The strengths of this study include 1) large-scale comprehensive molecular study design, 2) utilization of the high-quality resources within the MEC, and 3) the multi-disciplinary investigative team. Findings from this study will provide information on the biological mechanisms underlying the racial/ethnic disparities and evidentiary basis for the development of new personalized treatment targets and strategies to mitigate racial/ethnic disparities in lung cancer.