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，吸烟是主要的已知风险因素，并且生存率低，部分原因是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，以改善诊断后结果的研究是有希望的。然而，由于仅在美国就有超过9000万的活跃或戒烟者是筛查的候选人，因此潜在的成本非常高并且可能是令人望而却步的。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。根据人口统计学标准，可以确定一组10年肺癌风险超过20%的个体。即使在这样一个选定的群体中，对所有个体进行密切监测也是昂贵的，并且与假阳性结果的风险有关。在以前的研究中，我们报道了关键的抗氧化剂和DNA修复基因在肺癌病例的正常支气管上皮细胞（NBEC）中与非肺癌对照相比受到不同的调节。确定肺癌风险测试（LCRT），其包括在支气管镜检查时取样的NBEC中测量的14种关键抗氧化剂、DNA修复和转录因子基因的转录物丰度测量。该测试是在一项包括49名受试者（25名癌症受试者和24名对照受试者）的病例对照研究中发现的，并在包括40名受试者（20名病例和20名对照受试者）的第二项病例对照研究中得到验证。在这些研究中，该测试具有优于0.84的ROC AUC和大于20的优势比，用于识别具有超过20包年吸烟史的50岁以上患有肺癌的个体。该GO赠款的具体目标是：目标1。建立一项前瞻性队列巢式病例对照研究，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。入组至少1050例年龄超过50岁且吸烟史超过20包年但无肺癌患病率的受试者，这将导致识别出15例新发肺癌病例，每例病例随机选择8例对照。本研究将有足够的把握度（>80%）来检验比值比大于5.0。建立长期（10-20年）样本储存和分析以及受试者随访的计划和资源。目标2.建立NBEC和目标1入组受试者相应血液样本库。将存档NBEC的RNA、蛋白质和细胞学切片以及外周血白细胞RNA和DNA以及血液的冷冻血浆。在人口统计学定义的高风险组中识别将发展为肺癌的个体的生物标志物将能够进行更集中的选择，以进行更密切的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，将筛查限制在人口统计学和生物学风险最高的个体将显著降低实施成本。 公共卫生相关性：项目叙述这是一项验证多基因肺癌风险测试（LCRT）准确性的提案。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，使最高风险个体的登记，导致更低的假阳性和更低的试验成本。此外，如果筛选和/或化学预防方法得到验证，则可用于确定最有可能受益的个体，从而降低成本并降低不良事件的可能性。

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.