Biomarker Development Laboratory

项目摘要 这项BDL提案的目标是发现和验证生物标志物，以降低死亡率， 胃肠癌我们专注于结直肠癌（CRC），这是癌症死亡的第二大原因， 美国，食管腺癌（EAC），这是迅速增加，并有83%的死亡率。 对于CRC，我们建议开发生物标志物，以准确识别CRC高风险个体， 从积极的筛查项目中。我们将进行EDRN第1和第2阶段研究，以发现和验证 在正常结肠粘膜中发现的一类基于甲基化DNA的分子标记，我们先前的研究 与确定CRC风险增加的个体有关。对于EAC，我们建议识别生物标志物 这将准确检测食管细胞学样本中的高度异型增生（HGD）和早期EAC， 可以用非内窥镜设备获得，并且可以用于具有成本效益的BE监测计划。 第三，我们将进行EDRN 1期和2期研究，以发现和验证预测以下风险的生物标志物： 进展为HGD或早期EAC。我们的总体愿景是开发准确的基于生物标志物的测试， 最终可用于预测HGD和EAC风险并检测早期HGD的食管样本 和EAC使用非内镜食管细胞学样本实现经济有效的BE监测。 我们将这些1期和2期研究建立在我们鉴定的新型甲基化DNA生物标志物的基础上， 区分许多早期EAC和HGD从BE以及我们鉴定的候选甲基化DNA 与BE进展为HGD或EAC相关的标记和遗传标记。我们将制定一个最佳的 用于检测HGD和早期EAC的甲基化DNA标记物组。对于风险标记研究，我们将开发 一组甲基化DNA标记物和遗传标记物，用于预测BE进展为HGD的风险，或 EAC.因此，这项建议的具体目标是： 目标1。在EDRN 1/2期研究中评估一组候选生物标志物的敏感性和特异性 其在正常结肠粘膜中的检测鉴定出个体处于发展为晚期结肠炎的增加的风险中， 腺瘤或CRC。 目标2.在EDRN 1/2期研究中评估一组候选DNA甲基化的敏感性和特异性 用于鉴定Barrett食管的生物标志物、非整倍性标志物和拷贝数改变（CNA）标志物 有进展为HGD或EAC的风险 目标3.在EDRN 1/2期研究中开发一组用于检测早期EAC和HGD的候选生物标志物 以及食管细胞学样本中的“高风险”低度异型增生（LGD）。

PROJECT SUMMARY The goal of this BDL proposal is the discovery and validation of biomarkers for reducing mortality from gastrointestinal cancers. We focus on colorectal cancer (CRC), the second leading cause of cancer deaths in the U.S., and on esophageal adenocarcinoma (EAC), which is increasing rapidly and has an 83% mortality rate. For CRC, we propose to develop biomarkers to accurately identify individuals at high risk for CRC, who benefit from aggressive screening programs. We will conduct EDRN phase 1 and 2 studies to discover and validate a class of methylated DNA based molecular markers found in the normal colon mucosa, which our prior studies have implicated as identifying individuals at increased CRC risk. For EACs, we propose to identify biomarkers that will accurately detect high grade dysplasia (HGD) and early EAC in esophageal cytology samples, which can be obtained with a non-endoscopic device and can be used in a cost-effective BE surveillance program. Thirdly, we will conduct EDRN Phase 1 and 2 studies to discover and validate biomarkers that predict the risk of BE progressing to HGD or early EAC. Our overall vision is to develop accurate biomarker-based tests of esophageal samples that ultimately can be used to predict the risk for HGD and EAC and to detect early HGD and EAC to achieve cost-effective effective BE surveillance using non-endoscopic esophageal cytology samples. We base these Phase 1 and 2 studies on our identification of novel methylated DNA biomarkers that highly discriminate many early EAC and HGD from BE as well on our identification of candidate methylated DNA markers and genetic markers that associate with BE progression to HGD or EAC. We will develop an optimal panel of methylated DNA markers for detecting HGD and early EAC. For the risk marker studies, we will develop a panel of methylated DNA markers and genetic markers for predicting the risk of BE progressing to HGD or EAC. The specific aims of this proposal accordingly are: Aim 1. To assess in EDRN phase 1/2 studies, the sensitivity and specificity of a set of candidate biomarkers whose detection in the normal colon mucosa identifies individuals at increased risk of developing advanced adenoma or CRC. Aim 2. To assess in EDRN phase 1/2 studies the sensitivity and specificity of a set of candidate DNA methylation biomarkers, aneuploidy markers, and copy number alteration (CNA) markers for identifying Barrett’s esophagus that is at risk for progressing to HGD or EAC Aim 3. To develop in EDRN phase 1/2 studies a set of candidate biomarkers for detecting early EAC and HGD as well as “high-risk” low grade dysplasia (LGD) in esophageal cytology samples.