Project 2: Mitigating Lung Cancer Disparities in Native Hawaiians: A Population-Based Approach to Evaluate Prevention Barriers and Lung Tumor Biology

摘要 我们已经在多种族队列(MEC)中表明，夏威夷原住民患肺癌的风险明显更高 与(非西班牙裔)白人相比，癌症和疾病的存活率更低，即使在考虑到 吸烟史和其他风险/预后因素。这种额外的风险是在两种最常见的情况下观察到的 组织学细胞类型：腺癌和鳞癌以及小细胞肺癌， 侵略性细胞类型。早期而不是晚期患者的存活率较低。我们已经做出了 在遗传学、表观遗传学以及吸烟和烟草致癌物质相关生物标志物的研究方面做出了广泛努力 以了解不同人群患肺癌风险的差异。虽然非洲裔美国人的高风险 日裔美国人的低风险可以通过更高和更低的吸烟强度(致癌物剂量)来解释 每支香烟)，分别是由于吸烟行为和尼古丁代谢降低，导致风险超标 在夏威夷原住民中，人的情况仍有待阐明。低剂量CT在肺癌筛查中的应用 (LDCT)年龄在50岁至80岁之间、有20包吸烟史并目前吸烟的成年人，或 在过去15年内戒烟，已被发现可以降低死亡率。然而，夏威夷州排在最后 在早期被诊断为肺癌的比例(19%比全国平均水平24%)中， 超过3%的高危吸烟者接受LDCT扫描(全国平均为6%)。研究表明， 使用基于风险的预测模型可能比美国预防服务工作组更有效 (USPSTF)肺癌筛查中识别高危吸烟者的标准。然而，USPSTF和 指南和这些风险预测模型是从主要是欧洲血统的人收集的数据中得出的 人口。我们还发现，可能存在与致瘤性相关的不同生物学过程 导致夏威夷原住民风险过高和疾病结局不佳。我们观察到不同的 夏威夷原住民血液白细胞DNA表观遗传模式与吸烟剂量的比较 与其他种族/民族群体的差异甲基化发生在癌症相关基因中。以减少 关于夏威夷原住民的肺癌负担，我们建议进行一项多水平的翻译研究，以确定个人- 和基于提供者的肺癌筛查障碍，以制定干预策略，并在 与夏威夷卫生部合作(目标1)，以更好地识别罹患癌症风险最高的人群 通过计算夏威夷原住民特有的风险预测模型(AIM 2)，并对肿瘤进行表征 与夏威夷土著肺癌患者存活率低有关的病理生物学(目标3)。研究结果 将为高危少数群体提供肺癌医疗保健连续统一体的关键信息。 在这个赠款周期中，我们将开展合作，将我们的发现转化为经过验证的文化定制的 以精确度为基础的干预措施，以提高这种高危人群的早期发现和治疗方式的有效性 服务不足的少数族裔人口。

ABSTRACT We have shown in the Multiethnic Cohort (MEC) that Native Hawaiians have a markedly higher risk of lung cancer and a poorer survival from the disease compared to (non-Hispanic) Whites, even after accounting for smoking history and other risk/prognostic factors. This excess risk was observed for the two most common histologic cell-types: adenocarcinoma and squamous cell carcinoma as well as for small-cell lung cancer, a more aggressive cell-type. The poorer survival is observed with early stage and not advanced disease. We have made extensive efforts in the study of genetics, epigenetics and smoking and tobacco carcinogens-related biomarkers to understand the differences in lung cancer risk across populations. While the high risk in African Americans and low risk in Japanese Americans can be explained by higher and lower smoking intensity (carcinogens dose per cigarette), due to smoking behavior and lower nicotine metabolism, respectively, reasons for the risk excess in Native Hawaiians remain to be elucidated. Lung cancer screening using low-dose Computed Tomography (LDCT) among adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke, or have quit within the past 15 years, has been found to decrease mortality. However, the state of Hawaii ranks last in the proportion of lung cancers diagnosed at an early stage (19% vs. the national average of 24%), with less than 3% of high-risk smokers undergoing LDCT scan (national average is 6%). Studies have suggested that the use of risk-based prediction models may be more effective than the U.S. Preventive Services Task Force (USPSTF) criteria at identifying high-risk smokers for lung cancer screening. However, both the USPSTF guidelines and these risk prediction models were derived from data collected in mostly European-descent populations. We also found that there may be distinct biological processes related to tumorigenicity that contribute to the excess risk and poor disease outcomes for Native Hawaiians. We observed differences in epigenetic patterns in blood leukocyte DNA associated with smoking dose in Native Hawaiians when compared to other racial/ethnic groups, with the differential methylation occurring in cancer-related genes. To reduce the lung cancer burden of Native Hawaiians, we propose a multilevel translational study to identify the individual- and provider-based barriers for lung cancer screening to develop an intervention strategy to be disseminated in collaboration with the Hawaii Department of Health (Aim 1), to better identify those at greatest risk of developing lung cancer by computing a Native Hawaiian-specific risk prediction model (Aim 2), and to characterize the tumor pathobiology associated with the poor survival of Native Hawaiian lung cancer patients (Aim 3). Study findings will provide critical information along the continuum of lung cancer healthcare for a high risk minority population. During this grant cycle, we will develop collaborations to translate our findings into validated culturally-tailored, precision-based interventions to increase early detection and efficacy of treatment modalities in this high-risk underserved minority population.