Biomarker Development Laboratory

项目总结 这项BDL计划的目标是发现和验证生物标记物，以降低因 胃肠道癌症。我们的重点是结直肠癌(CRC)，这是#年癌症死亡的第二大原因。 在美国，食管腺癌(EAC)正在迅速增加，死亡率高达83%。 对于结直肠癌，我们建议开发生物标志物，以准确地识别结直肠癌的高危个体，他们受益于 来自激进的筛查项目。我们将进行EDRN阶段1和2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 已经牵涉到识别具有更高的CRC风险的个人。对于EACS，我们建议识别生物标记物 这将准确检测食道细胞学样本中的高度不典型增生(HGD)和早期EAC， 可以用非内窥镜设备获得，并可以用于成本效益高的BE监测计划。 第三，我们将进行EDRN阶段1和2研究，以发现和验证预测糖尿病风险的生物标志物 进展到HGD或早期EAC。我们的总体愿景是开发基于生物标记物的准确测试 最终可用于预测HGD和EAC的风险以及检测早期HGD的食道样本 和EAC使用非内窥镜食道细胞学样本实现具有成本效益的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生物标记物的基础上 从候选甲基化DNA的鉴定中区分许多早期EAC和HGD与BE 与BE进展为HGD或EAC相关的标记和遗传标记。我们将开发一种最佳的 检测HGD和早期EAC的甲基化DNA标记组合。对于风险标记物研究，我们将开发 一组甲基化DNA标记和遗传标记用于预测BE进展为HGD或 EAC。因此，这项建议的具体目标是： 目的1.在EDRN 1/2期研究中，评估一组候选生物标记物的敏感性和特异性 其在正常结肠粘膜中的检测可确定有较高风险发展为晚期的个体。 腺瘤或结直肠癌。 目的2.在EDRN阶段1/2中评估一组候选DNA甲基化的敏感性和特异性 生物标记物、非整倍体标记物和拷贝数改变(CNA)标记物用于Barrett‘s食道的鉴定 这有可能发展为HGD或EAC 目的3.在EDRN阶段1/2研究一组检测早期EAC和HGD的候选生物标志物 以及“高危”低度异型增生(LGD)的食道细胞学样本。

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.