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

摘要 肺癌是第二大常见癌症，也是两人癌症相关死亡的主要原因 美国所有主要种族/族裔群体的妇女。吸烟是肺部最大的危险因素 癌然而，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土著人的疾病风险较高 与白人相比，日裔美国人和拉丁美洲人的风险较低。肺癌是一 具有四种主要组织学细胞类型异质性疾病和种族/民族差异在所有细胞中持续存在， 类型我们已经报道了吸烟相关肺癌中导致这些差异的机制 风险，我们检查了生活方式和健康行为，吸烟的内部生物剂量及其致癌物， 以及吸烟对多种族人群血液白细胞DNA甲基化的影响。在 最近的一项研究报告了基因表达谱，以比较非裔美国人和白人的肺ADC， 他们发现非裔美国人肺ADC肿瘤的肿瘤生物学差异， 这表明种族/民族差异可能反映在潜在的肺部肿瘤的差异中， 生物学然而，到目前为止，包括其他少数民族人口的全面分子研究还没有 进行了。因此，该提案的目标是对最常见的肺癌细胞类型进行分子分析， ADC，来自MEC中的五个种族/民族组，以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。为了我们的第一个目标，我们将进行一次全面的 使用肺ADC进行全基因组DNA甲基化和转录组分析，以了解人种/种族差异 来自750例多种族肺癌病例（非裔美国人、拉丁美洲人、夏威夷土著人、日本人）的肿瘤组织 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， 肿瘤分期对于我们的第二个目标，我们将研究DNA甲基化和转录组学之间的关系。 肺ADC肿瘤与肺ADC生存率的曲线和人种/种族的效应修饰。对于第三个目标， 我们将研究DNA甲基化和转录组学谱是否介导了 人种/种族和肺ADC生存率。此外，我们将整合DNA甲基化，转录组学，风险因子， 和死亡数据，以确定与疾病生存相关的新的肺癌亚组。这种做法的优点是， 研究内容包括：1）大规模的综合分子研究设计; 2）优质资源的利用 3）多学科调查小组。这项研究的结果将提供信息， 种族/族裔差异的生物学机制和发展的证据基础 新的个性化治疗目标和策略，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.