Comprehensive Biomarker Development in early Esophagogas

早期食管气的综合生物标志物开发

• 批准号: 6951228
• 负责人: Stephen J Meltzer
• 金额: $ 44.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951228
• 关键词: Barretts esophagus; adenocarcinoma; biomarker; cancer registry /resource; clinical research; cooperative study; diagnosis design /evaluation; early diagnosis; esophagogastric junction; esophagus neoplasm; fluid flow; gene expression; gene expression profiling; human tissue; metaplasia; microarray technology; molecular oncology; molecular pathology; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; neoplastic process; patient oriented research; polymerase chain reaction; preneoplastic state; stomach neoplasms

DESCRIPTION (provided by applicant): Esophageal and gastric carcinomas are among the top ten causes of cancer death worldwide. These diseases are usually detected at advanced stages, when available treatments are not very effective. Earlier detection of these cancers has been shown to make a significant impact on patient outcome. Our preliminary studies have discovered biomarkers that can diagnose synchronous cancer from normal or premalignant tissues. We will extend these studies to confirm that these same biomarkers can predict future (metachronous) esophagogastric cancer risk. This application will have as its ultimate goal the translation of these early detection biomarkers into clinical validation within 5 years. Aim 1. In pilot cohort Phase I discovery studies using cDNA microarrays, to develop biomarkers distinguishing between normal or metaplastic tissues of patients with vs. without cancer. Aim 1.a. In a cohort of 20 patients without Barrett's or cancer, 20 with Barrett's only, and 20 with Barrett's adenocarcinoma, using the shrunken nearest centroids predictor (SNCP) model, to identify gene expression panels and individual gene biomarkers to distinguish between patients with and without esophageal cancer. Aim 1.b. In 20 patients without and 20 with gastric cancer, using the SNCP model, to identify gene expression panels and individual gene biomarkers distinguishing between patients with and without gastric cancer. Aim 1.c. To determine the positive predictive value (PPV) of all potential biomarkers identified in Aims 1.a. and 1.b. Aim 2. In a pilot cohort Phase II validation study, to confirm expression panels and individual genes identified in Aim 1 with quantitative RT-PCR (Q-PCR) using a capillary microfluidics station-based method. Aim 2.a. To perform analytical validation of Q-PCR by checking its sensitivity in detecting a positive signal, its dynamic range, and its reproducibility in repeat analyses. Aim 2.b. To perform microfluidics measurement of gene expression levels from paraffin-derived esophageal tissues matched to the 60 frozen specimens studied in Aim 1.a. Aim 2.c. To perform microfluidics measurements of gene expression levels from paraffin-derived gastric tissues matched to the 60 frozen specimens studied in Aim 1.b. Aim 3. In larger cohorts, to perform Phase III cross-sectional retrospective longitudinal validation studies using the QPCR method analytically validated in Aim 2. Aim 3.a. To perform a Phase III study (n=400) of 200 esophageal cancer and 200 Barrett's patients, including 127 patients from whom tissues were obtained prior to a cancer diagnosis. Aim 3.b. To perform a Phase III study (n=200) of 100 gastric cancer and 100 noncancer patients. Aim 3.c. To perform statistical analyses of data from Aims 3.a. and 3.b. in order to determine their validity and significance.

描述（由申请人提供）：食道和胃癌是全球癌症死亡的十大原因之一。 这些疾病通常在高级阶段检测到，如果可用的治疗不是很好。早期发现这些癌症对患者结局产生了重大影响。我们的初步研究发现了可以诊断出正常或抗态度组织的同步癌的生物标志物。 我们将扩展这些研究，以确认这些相同的生物标志物可以预测未来（常规）食管胃癌风险。 该应用将作为其最终目标在5年内将这些早期检测生物标志物转化为临床验证。 AIM1。在I阶段的I阶段发现研究中，使用cDNA微阵列开发出区分患有无癌患者的正常或变质组织组织的生物标志物。目标1.A.在20名没有巴雷特或癌症的患者组中，只有20名与巴雷特的患者一起使用，其中20例使用缩水的最近的质心预测因子（SNCP）模型，与Barrett的腺癌组成，以识别基因表达面板和单个基因生物标志物，以区分患有和没有食管癌的患者。 目标1.B.在20例没有SNCP模型的患者和20例胃癌患者中，鉴定了区分和没有胃癌患者的基因表达板和单个基因生物标志物。 AIM 1.C.确定目标1.A中确定的所有潜在生物标志物的阳性预测值（PPV）。和1.b。 AIM 2。在Pilot队列II期验证研究中，使用基于毛细管微流体电池站基于定量的RT-PCR（Q-PCR）在AIM 1中确定的表达面板和单个基因。 目标2.A.通过检查其在检测正信号，动态范围和重复分析中的可重复性时，通过检查其灵敏度来对其进行分析验证。 AIM 2.B.从石蜡衍生的食管组织中对基因表达水平进行微流体测量，与AIM 1.A中研究的60个冷冻标本相匹配。 AIM 2.C.从石蜡衍生的胃组织中对基因表达水平进行微流体测量，该胃组织与AIM 1.B中研究的60个冷冻标本相匹配。 AIM 3。在较大的队列中，使用AIM 2中对QPCR方法进行分析验证的QPCR方法进行III期横截面回顾性纵向验证研究。 目标3.A.为了进行200例食管癌和200例Barrett患者的III期研究（n = 400），其中包括127名患者，在癌症诊断之前获得了组织。 AIM 3.B.对100例胃癌和100名非癌患者进行III期研究（n = 200）。 AIM 3.C.对AIM 3.A的数据进行统计分析。和3.b。为了确定其有效性和意义。