Profiling autoantibodies for early detection of esophageal squamous cell carcinom

描述(申请人提供)：食道鳞状细胞癌(ESCC)是世界上最常见的致命性癌症之一，其5年生存率为15%。要显著降低死亡率，将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。这项应用的目标是开发一种基于血液的筛查试验，使用疾病相关自身抗体作为高危人群早期ESCC的生物标记物。我们已经开发了一种类似的早期检测非小细胞肺癌(NSCLC)的方法，对诊断I期NSCLC的敏感性和特异性超过91%。通过与国家癌症研究所的Sanford Dawsey博士和Philip Taylor博士合作，他们在过去20年里领导了中国高危地区的食道癌流行病学研究，我们获得了来自ESCC和鳞状上皮不典型增生各个阶段的患者以及高危“正常”个人的大量血清样本。在我们的初步研究中，我们从肿瘤组织中构建了一个ESCC T7噬菌体展示文库，并用患者和正常血清对该文库进行了生物扫描，以丰富仅在病例中发现的与自身抗体结合的肿瘤相关蛋白。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，该系统可以用于高通量发现和验证疾病分类器。我们的初步测试在检测ESCC方面显示了有希望的结果。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记芯片。将进行统计分析，并将生成分类器以区分病例和对照。其次，这些分类器将以盲法交叉验证的方式评估它们的能力：1)在由200名ESCC患者和200名对照组成的单独验证集中区分ESCC和非癌样本；2)使用来自150名有这些病变的患者和150名没有这些病变的患者的样本，识别食道鳞状上皮不典型增生，ESCC的前驱病变和早期癌症；以及3)使用从200名在样本收集3年内有过这些病变的患者和200名没有发生ESCC的患者的前瞻性样本来识别未来将发展为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进行临床方案，在那里我们有持续的合作和执行此类研究的基础设施。公共卫生相关性：食道鳞状细胞癌是全世界最常见的致命癌症之一。要降低死亡率，就必须采取成功的策略，及早发现这种疾病。这项研究的目标是开发一种血液测试，可以使用疾病相关自身抗体作为生物标记物来检测早期食管鳞癌。

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.