Validation of a multi-gene test for lung cancer risk

描述(申请人提供)：肺癌是美国男性和女性癌症死亡的主要原因，吸烟是主要的已知风险因素，存活率低的部分原因是当第一次发现和治疗时，肺癌通常处于晚期。通过低剂量螺旋CT筛查和外科手术早期发现改善肺癌诊断后预后的研究是很有前途的。然而，由于仅在美国就有9000多万活跃或曾经吸烟者是筛查对象，潜在的成本非常高，可能令人望而却步。此外，到目前为止完成的CT筛查研究与假阳性结果的高发生率有关，这可能导致不必要的后续诊断测试。根据人口统计学标准，可以确定一组人患肺癌的10年风险超过20%。即使是在这样一个被选中的群体中，对所有个人进行密切监测也是代价高昂的，并与假阳性结果的风险有关。在以前的研究中，我们报道了与非肺癌对照相比，肺癌患者正常支气管上皮细胞(NBEC)中关键的抗氧化剂和DNA修复基因受到不同的调控。肺癌风险测试(LCRT)包括14个关键抗氧化剂、DNA修复和转录因子基因的转录丰度测量，这些基因是在支气管镜检查时采集的NBEC中测量的。这项测试是在一项病例对照研究中发现的，该研究包括49名受试者(25名癌症患者和24名对照)，并在第二项病例对照研究中得到验证，该研究包括40名受试者(20例病例和20名对照)。在这些研究中，对于50岁以上、吸烟史超过20年的肺癌患者，该测试的ROC AUC优于0.84，优势比超过20。这项GO赠款的具体目的是：目的1.建立一项前瞻性队列嵌套病例对照研究，以测试肺癌风险测试(LCRT)的有效性，该测试包含在支气管镜检查获得的正常呼吸道上皮细胞中测量的14个基因。招募至少1050名年龄在50岁以上、吸烟史超过20年但没有肺癌患病率的受试者，这将导致识别15例肺癌病例，每个病例随机选择8名对照。这项研究将有足够的力量(80%)来测试超过5.0的赔率比。制定长期(10-20年)样品存储和分析以及主题跟踪的计划和资源。目的2.建立NBEC及其相应的血液样本资料库。NBEC的RNA、蛋白质和细胞学玻片及外周血白细胞RNA、DNA和冰冻血浆将被存档。识别人口统计学定义的高危人群中将患肺癌的个人的生物标记物将使更有针对性的选择能够更密切地监测，并进一步降低假阳性结果的风险。此外，如果CT筛查得到验证，将筛查限制在人口和生物风险最高的个人将显著降低实施成本。 公共卫生相关性：项目描述这是一项验证多基因肺癌风险测试(LCRT)准确性的建议。准确的LCRT可用于设计更有效的肺癌筛查和/或化学预防研究，因为它允许登记最高风险的个人，从而导致较低的假阳性和较低的试验成本。此外，如果一种筛查和/或化学预防方法得到验证，它可以用于确定最有可能受益的个人，从而降低成本和减少不良事件的可能性。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer mortality in both men and women in the United States with cigarette smoking being the primary known risk factor and has a low survival rate in part because it typically is at an advanced stage when first detected and treated. Studies to improve post-diagnosis outcome of lung cancer through early detection by means of low-dose spiral coaxial tomography (CT) screening and surgical intervention are promising. However, because more than 90 million active or ex-smokers in the United States alone are candidates for screening the potential cost is very high and may be prohibitive. Additionally, CT screening studies completed thus far are associated with a high incidence of false positive findings which may lead to unnecessary follow-up diagnostic testing. Based on demographic criteria it is possible to identify a group of individuals for whom the 10 year risk for lung cancer is more than 20%. Even in a group as selected as this, subjecting all individuals to close monitoring is costly and is associated with risk of false positive results. In previous studies we reported that key antioxidant and DNA repair genes are regulated differently in normal bronchial epithelial cells (NBEC) of lung cancer cases compared to non-lung cancer controls. A Lung Cancer Risk Test (LCRT) was identified comprising transcript abundance measurement of 14 key antioxidant, DNA repair and transcription factor genes measured in NBEC sampled at the time of bronchoscopy. The test was discovered in a case control study comprising 49 subjects (25 cancer and 24 controls) and validated in a second case-control study comprising 40 subjects (20 cases and 20 controls). In these studies the test had ROC AUC of better than 0.84 and odds ratio of more than 20 for identifying individuals over the age of 50 with more than 20 pack years smoking history who have lung cancer. The Specific Aims of this GO grant are: Aim 1. Establish a prospective cohort nested case control study to test the validity of a lung cancer risk test (LCRT) comprising 14 genes measured in normal airway epithelial cells obtained at bronchoscopy. Enroll at least 1050 subjects over the age of 50 and with more than 20 pack year smoking history but without prevalence lung cancer which will result in identification of 15 incident lung cancer cases with eight randomly selected controls for each case. This study will have sufficient power (>80%) to test an Odds Ratio of greater than 5.0. Establish a plan and resources for long-term (10-20 years) sample storage and analysis and subject follow-up. Aim 2. Establish a bank of NBEC and corresponding blood samples from the subjects enrolled in Aim 1. RNA, protein, and cytology slides from NBEC and peripheral blood leukocyte RNA and DNA and frozen plasma from blood will be archived. A biomarker that identifies individuals within a demographically defined high risk group who will develop lung cancer will enable even more focused selection for closer monitoring and further reduction in risk of false positive findings. Further, if CT screening is validated, limiting screening to the individuals with the highest demographic and biological risk will markedly reduce cost of implementation. PUBLIC HEALTH RELEVANCE: Project Narrative this is a proposal to validate the accuracy of a multi-gene Lung Cancer Risk Test (LCRT). An accurate LCRT may be used to design more efficient lung cancer screening and/or chemoprevention studies by enabling enrollment of the highest risk individuals, resulting in lower false positives and lower trial costs. In addition, if and when a screening and/or chemoprevention method is validated, it may be used to identify the individuals most likely to benefit, resulting in lower cost and reduced likelihood of adverse events.