Biomarker Development Laboratory

生物标志物开发实验室

• 批准号: 10677827
• 负责人: William Mallory Grady
• 金额: $ 32.76万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677827
• 关键词: Age; Aneuploidy; Barrett Esophagus; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Cancer Etiology; Cessation of life; Clinical; Colon; Colon Carcinoma; Colonic Adenoma; Colonoscopy; Colorectal Cancer; Cytology; DNA; DNA Markers; DNA Methylation; Data; Detection; Devices; Dysplasia; Early Detection Research Network; Early Diagnosis; Esophageal Adenocarcinoma; Esophagus; Funding; Genetic Markers; Goals; High grade dysplasia; Incidence; Individual; Lesion; Life; Malignant neoplasm of esophagus; Malignant neoplasm of gastrointestinal tract; Methylation; Molecular; Mucous Membrane; Natural History; Patients; Performance; Persons; Phase; Prevention; Progressive Disease; Prospective cohort; Recurrence; Retrospective cohort study; Risk; Risk Marker; Sampling; Screening for cancer; Sensitivity and Specificity; Stable Disease; Surveillance Program; Testing; Vision; adenoma; base; biomarker development; biomarker identification; biomarker validation; cancer therapy; candidate identification; candidate marker; clinically relevant; cohort; colon cancer risk; colon cancer screening; colorectal cancer risk; colorectal cancer screening; cost effective; early detection biomarkers; follow-up; genomic locus; high risk; laboratory development; methylation biomarker; molecular marker; mortality; novel; phase IV trial; predictive marker; progression risk; prospective; risk prediction; risk stratification; risk variant; screening; screening program

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.

项目概要 该 BDL 提案的目标是发现和验证生物标志物，以降低死亡率 我们重点关注结直肠癌 (CRC)，它是导致癌症死亡的第二大原因。 美国的食管腺癌 (EAC) 增长迅速，死亡率高达 83%。 对于结直肠癌，我们建议开发生物标志物来准确识别结直肠癌高危人群，使他们受益 我们将进行 EDRN 第一阶段和第二阶段研究，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，我们之前的研究 对于 EAC，我们建议识别生物标志物。 将准确检测食管细胞学样本中的高度不典型增生 (HGD) 和早期 EAC， 可以通过非内窥镜设备获得，并且可以用于具有成本效益的 BE 监视计划。 第三，我们将进行 EDRN 第一期和第二期研究，以发现和验证预测风险的生物标志物 BE 进展到 HGD 或早期 EAC。我们的总体愿景是开发基于生物标志物的准确测试。 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 使用非内窥镜食管细胞学样本实现经济有效的 BE 监测。 我们的这些 1 期和 2 期研究基于我们对新型甲基化 DNA 生物标志物的鉴定，这些生物标志物高度 区分许多早期 EAC 和 HGD 与 BE 以及我们对候选甲基化 DNA 的识别 我们将开发一个最佳的与 BE 进展为 HGD 或 EAC 相关的标记和遗传标记。 我们将开发用于检测 HGD 和早期 EAC 的甲基化 DNA 标记物组。 一组甲基化 DNA 标记和遗传标记，用于预测 BE 进展为 HGD 的风险或 因此，EAC 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 在正常结肠粘膜中的检测可识别出罹患晚期癌症的风险增加的个体 腺瘤或结直肠癌。 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 用于识别巴雷特食管的生物标志物、非整倍体标志物和拷贝数改变 (CNA) 标志物 有进展为 HGD 或 EAC 风险的人 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”低度不典型增生（LGD）。