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

摘要 我们在多种族队列（MEC）中发现，夏威夷土著人患肺癌的风险明显较高， 与（非西班牙裔）白人相比，癌症和疾病的生存率更低，即使在考虑了 吸烟史和其他风险/预后因素。这种过度风险是在两种最常见的 组织细胞类型：腺癌和鳞状细胞癌以及小细胞肺癌， 攻击性细胞类型在早期而非晚期疾病中观察到较差的生存率。我们取得了 在遗传学、表观遗传学、吸烟和烟草致癌物相关生物标志物的研究方面做出了广泛努力 了解不同人群肺癌风险的差异。虽然非裔美国人的高风险 日裔美国人的低风险可以解释为较高和较低的吸烟强度（致癌物剂量 每支香烟），由于吸烟行为和降低尼古丁代谢，分别为风险过剩的原因 在夏威夷原住民身上的作用有待进一步阐明低剂量CT在肺癌筛查中的应用 （LDCT）在50至80岁的成年人中，有20包年吸烟史，目前吸烟，或 在过去的15年内戒烟，已经被发现可以降低死亡率。然而，夏威夷州排名最后 在早期阶段诊断出肺癌的比例（19%，全国平均水平为24%）， 超过3%的高危吸烟者接受LDCT扫描（全国平均水平为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）标准，用于识别肺癌筛查的高危吸烟者。然而，USPSTF 指南和这些风险预测模型是从收集的数据，主要是欧洲裔 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， 导致夏威夷原住民的过度风险和不良疾病后果。我们观察到 夏威夷土著人与吸烟剂量相关的血液白细胞DNA的表观遗传模式 与其他种族/族裔群体相比，癌症相关基因中存在差异甲基化。减少 夏威夷原住民的肺癌负担，我们提出了一个多层次的翻译研究，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， 与夏威夷卫生部合作（目标1），以更好地确定那些最有可能发展为 肺癌通过计算夏威夷本地特定的风险预测模型（目标2），并表征肿瘤 病理生物学与夏威夷土著肺癌患者的不良存活率相关（目的3）。研究结果 将提供关键信息沿着连续的肺癌医疗保健的高风险少数群体。 在这个资助周期中，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， 基于精确的干预措施，以增加这种高风险患者的早期发现和治疗方式的疗效 服务不足的少数民族。

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.