Profiling autoantibodies for early detection of esophageal squamous cell carcinom

描述（申请人提供）：食管鳞状细胞癌（ESCC）是全球最常见的致命性癌症之一，其5年生存率<15%。死亡率的显著降低需要成功的策略来诊断和治疗无症状的前驱病变和早期癌症。本申请的目的是开发一种基于血液的筛查方法，使用疾病相关的自身抗体作为高危人群中早期ESCC的生物标志物。我们已经开发了一种用于早期检测非小细胞肺癌（NSCLC）的类似检测方法，其诊断I期NSCLC的灵敏度和特异性超过91%。通过与NCI的Sanford Dawsey和Philip Taylor博士（他们在过去20年中领导了中国高危地区的食管癌流行病学研究）的合作，我们获得了来自ESCC和鳞状不典型增生各个阶段患者以及高危“正常”个体的大量血清样本。在我们的初步研究中，我们已经构建了一个ESCC T7噬菌体展示库从肿瘤组织，并与患者和正常血清的生物淘选这个库，以丰富的肿瘤相关蛋白结合的自身抗体，发现只有在案件。我们在一个双色荧光微阵列系统上发现了2000个这样的蛋白质，该系统可用于高通量发现和疾病分类器的验证。我们的初步测试表明，在检测ESCC方面取得了令人鼓舞的结果。在这项研究中，我们将首先使用100个ESCC和100个对照血清样本作为训练集来测试我们的生物标志物芯片。将进行统计分析，并生成分类器以区分病例和对照。其次，将在盲交叉验证中评估这些分类器的以下能力：1）在200名ESCC患者和200名对照的单独验证集中区分ESCC与非癌症样本; 2）使用来自150名患有和150名没有这些病变的患者的样本识别食管鳞状上皮发育不良、ESCC的前驱病变和早期癌症;和3）使用从200名在样本收集的3年内发生ESCC的患者和200名未发生ESCC的患者中前瞻性收集的样本，鉴定将来将发生ESCC的无症状患者。如果这些研究的结果是有希望的，我们将继续在高风险地区的临床协议，我们有正在进行的合作和基础设施，以执行此类研究。公共卫生相关性：食管鳞状细胞癌是全球最常见的致命癌症之一。降低死亡率需要成功的策略，早期发现这种疾病。本研究的目的是开发一种血液检测，可以检测早期阶段的食管鳞状细胞癌使用疾病相关的自身抗体作为生物标志物。

DESCRIPTION (provided by applicant): Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal cancers worldwide, which has a 5-year survival rate of <15%. Significant reduction in the mortality will require successful strategies to diagnose and treat asymptomatic precursor lesions and early stage cancers. The goal of this application is to develop a blood-based screening assay using disease-associated autoantibodies as biomarkers for early stage ESCC in high-risk populations. We have developed a similar test for early detection of non-small cell lung cancer (NSCLC), which achieved over 91% sensitivity and specificity for diagnosing stage I NSCLC. Through collaboration with Drs. Sanford Dawsey and Philip Taylor at the NCI, who have led esophageal cancer epidemiologic studies in high- risk regions in China over the last twenty years, we have access to a large number of serum samples from patients at all stages of ESCC and squamous dysplasia, and from high-risk "normal" individuals. In our preliminary study, we have constructed an ESCC T7 phage-display library from tumor tissues, and have biopanned this library with patient and normal sera to enrich tumor-associated proteins that bind to autoantibodies found only in the cases. We spotted 2000 of these proteins on a two-color fluorescent microarray system that can be used for high-throughput discovery and validation of disease classifiers. Our preliminary testing has demonstrated promising results in detecting ESCC. In this study we will first test our biomarker chips with 100 ESCC and 100 control serum samples, as a training set. Statistical analysis will be performed and classifiers will be generated for discriminating cases from controls. Second, these classifiers will be evaluated in a blind cross-validation for their ability to: 1) discriminate ESCC from non-cancer samples in a separate validation set of 200 ESCC patients and 200 controls; 2) identify esophageal squamous dysplasia, the precursor lesion of ESCC, and early-stage cancers, using samples from 150 patients with and 150 patients without these lesions; and 3) identify asymptomatic patients who will develop ESCC in the future, using prospectively collected samples from 200 such patients who did and 200 patients who did not develop ESCC within 3 years of sample collection. If the results of these studies are promising, we will proceed to clinical protocols in the high-risk regions where we have ongoing collaborations and the infrastructure to perform such studies. PUBLIC HEALTH RELEVANCE: Esophageal squamous cell carcinoma is one of the most common fatal cancers worldwide. Reduction of the mortality requires successful strategies for early detection of this disease. The goal of this study is to develop a blood test that can detect early stages of esophageal squamous cell carcinoma using disease associated autoantibodies as biomarkers.