Validation of a multi-gene test for lung cancer risk

描述（由申请人提供）：肺癌是美国男性和女性癌症死亡的主要原因，吸烟是已知的主要危险因素，生存率低，部分原因是肺癌在首次发现和治疗时通常处于晚期。通过低剂量螺旋同轴断层扫描（CT）筛查和手术干预早期发现肺癌，改善其诊断后预后的研究是有前景的。然而，由于仅在美国就有超过9000万的活跃吸烟者或戒烟者是筛查的候选人，潜在的成本非常高，可能令人望而却步。此外，迄今为止完成的CT筛查研究与假阳性结果的高发生率相关，这可能导致不必要的后续诊断测试。根据人口统计标准，有可能确定一个10年患肺癌风险超过20%的人群。即使在这样一个被选中的群体中，对所有个体进行密切监测也是代价高昂的，而且与假阳性结果的风险有关。在之前的研究中，我们报道了肺癌患者正常支气管上皮细胞（NBEC）中关键的抗氧化和DNA修复基因与非肺癌对照组的调控不同。肺癌风险测试（LCRT）包括在支气管镜检查时取样的NBEC中测量的14个关键抗氧化、DNA修复和转录因子基因的转录丰度测量。该测试是在一项包含49名受试者（25名癌症患者和24名对照患者）的病例对照研究中发现的，并在另一项包含40名受试者（20名患者和20名对照患者）的病例对照研究中得到验证。在这些研究中，该测试的ROC AUC大于0.84，比值比大于20，用于识别50岁以上吸烟史超过20包年的肺癌患者。这个GO赠款的具体目标是：目标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，该测试包括在支气管镜检查获得的正常气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包年，但没有肺癌患病率的受试者，这将导致确定15例肺癌病例，每个病例随机选择8例对照。这项研究将有足够的力量（bbb80 %）来检验大于5.0的优势比。建立长期（10-20年）样品储存分析和受试者随访的计划和资源。目标2。建立NBEC库，并从第1阶段受试者中提取相应的血液样本。NBEC的RNA、蛋白质和细胞学切片和外周血白细胞的RNA和DNA以及血液中的冷冻血浆将被存档。一种生物标志物可以识别人口统计学定义的高风险群体中的个体，这些个体将发展为肺癌，这将使更有针对性的选择更加密切的监测和进一步降低假阳性结果的风险。此外，如果CT筛查得到验证，将筛查限制在人口统计学和生物学风险最高的个体将显著降低实施成本。

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.