Validation of Methylated Vimentin as a Diagnostic Test for Barrett's Esophagus

甲基化波形蛋白作为巴雷特食管诊断测试的验证

• 批准号: 9923576
• 负责人: JOSEPH EDWARD WILLIS
• 金额: $ 33.22万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-26 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923576
• 关键词: Affect; Barrett Esophagus; Biological Assay; Biological Markers; Biopsy; CLIA certified; Characteristics; Clinical; Clinical Management; Clinical Trials; Collection; Companions; Credentialing; Cytology; DNA; Detection; Devices; Diagnosis; Diagnostic tests; Dideoxy Chain Termination DNA Sequencing; Disease; Distal; Early Diagnosis; Endoscopy; Engineering; Enrollment; Esophageal Adenocarcinoma; Esophagus; Etiology; Future; High grade dysplasia; Human; Incidence; Individual; Laboratories; Laboratory Research; Legal patent; Malignant Neoplasms; Medical; Medical center; Methods; Methylation; Molecular; Neoplasms; Ohio; Operative Surgical Procedures; Outcome; Outpatients; Pathologic; Pathology; Patients; Performance; Phase; Population; Prevention; Protocols documentation; Reflux; Sampling; Screening procedure; Sedation procedure; Sensitivity and Specificity; Services; Specimen; Specimen Handling; Surveillance Program; Symptoms; Technology; Test Result; Testing; Therapeutic; Therapeutic Intervention; Time; Universities; University Hospitals; Upper digestive tract structure; Validation; Vimentin; base; bisulfite; bisulfite sequencing; commercialization; cost; high risk population; molecular diagnostics; mortality; next generation; next generation sequencing; novel; programs; prospective; public health relevance; research clinical testing; routine screening; screening; specific biomarkers; tertiary care

 DESCRIPTION (provided by applicant): Esophageal adenocarcinoma [EAC] incidence has increased by at least four fold over the last three decades and is increasing by 1-2% annually. It is also one the most lethal cancers - as eighty percent of EAC patients die of their disease - most within 2 years of diagnosis. These dismal outcomes occur in spite improvements in surgical and endoscopic therapies. It is extremely unlikely that advances in cancer therapeutics - without progress in early detection and prevention - will have a significant impact on this high mortality rate in the near future. Barrett's Esophagus [BE], defined as intestinal metaplasia [IM] of the esophagus, is the only established precursor of EAC and is diagnosed via upper GI endoscopy [EGD] and biopsy. Due to high cost of EGD, screening even in patients with reflux is not routinely performed. Thus less than 5% of EACs are diagnosed in individuals with previously detected BE. Most BE remains undetected though it affects up to 7% of the population. We have identified a biomarker, aberrantly methylated vimentin [mVIM], which has greater than 90% sensitivity and specificity for BE in upper GI samples. The detection of this marker in upper GI tract samples is eminently feasible using current technologies. The UH2 portion will validate this marker on two platforms - methylation specific real time PCR and methylation specific NGS. This validation will occur at Case Medical Center with the support of the discoverers of mVIM at Case Western Reserve University [CWRU]. Laboratory validation will occur using established CLIA/CAP standards The UH3 portion will clinically validate the mVIM assay based on two clinical trials accessing esophageal cytology samples as a method for screening for BE. The trials will look at two patient groups: known BE patients vs. controls; and patients presenting with upper GI symptoms. A novel component of these trials is the use of a balloon device invented at CWRU for the purpose of obtaining samples of the distal esophagus without sedation and with minimal discomfort. In pre-human testing the device gave x10 the DNA needed for the proposed assays. The combination of an easy to use, efficient esophageal sampling device and a CLIA approved Laboratory Developed Test offers a real chance to identify asymptomatic individuals with BE, allowing them an opportunity to be enrolled in BE surveillance programs before the onset of EAC. Based on initial testing the laboratory and clinical validations will have sensitivities and specificities sufficient to allow for follow-on stps leading to commercialization.

 描述（由申请方提供）：在过去三十年中，食管腺癌[EAC]的发病率至少增加了四倍，并且每年增加1-2%。它也是最致命的癌症之一-因为80%的EAC患者死于他们的疾病-大多数在诊断后2年内。尽管手术和内窥镜治疗有所改进，但仍发生了这些令人沮丧的结局。癌症治疗的进步--如果没有早期发现和预防方面的进步--在不久的将来对这种高死亡率产生重大影响的可能性微乎其微。Barrett食管[BE]定义为食管的肠上皮化生[IM]，是EAC唯一确定的前体，通过上消化道内镜[EGD]和活检诊断。由于EGD的高成本，即使在反流患者中也不进行常规筛查。因此，在先前检测到BE的个体中诊断出不到5%的EAC。大多数BE仍然未被发现，尽管它影响高达7%的人口。我们已经确定了一种生物标志物，异常甲基化波形蛋白[mVIM]，其在上消化道样本中对BE的敏感性和特异性大于90%。使用当前技术在上消化道样品中检测该标志物是非常可行的。UH 2部分将在两个平台上验证该标记物-甲基化特异性真实的时间PCR和甲基化特异性NGS。该验证将在凯斯西储大学[CWRU]的mVIM发现者的支持下在凯斯医疗中心进行。将使用已建立的CLIA/CAP标准进行实验室验证。UH 3部分将根据两项临床试验对mVIM检测进行临床验证，这些试验将食管细胞学样本作为BE筛查方法。这些试验将观察两个患者组：已知的BE患者与对照组;以及出现上消化道症状的患者。这些试验的一个新组成部分是使用CWRU发明的球囊装置，目的是在没有镇静和最小不适的情况下获得远端食管样本。在人类前测试中，该设备提供了x10所需的DNA用于拟议的测定。易于使用、高效的食管采样装置与CLIA批准的实验室开发检测相结合，为识别无症状BE患者提供了真实的机会，使他们有机会在EAC发作前参加BE监测项目。基于初始测试，实验室和临床验证将具有足够的灵敏度和特异性，以允许后续stp导致商业化。