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Development of diagnostic and prognostic tests for esophageal adenocarcinoma

食管腺癌诊断和预后测试的发展

基本信息

批准号：
10308014
负责人：
Tony E Godfrey
金额：
$ 24.06万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-16 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308014
关键词：
Address Alleles Barrett Esophagus Biological Assay Biological Markers Biopsy Canada Cells Chromosomal Rearrangement Chronic Clinical Collection Curative Surgery Cytology DNA DNA copy number Data Deglutition Detection Development Devices Diagnosis Diagnostic tests Disease Disease Progression Dysplasia Early Diagnosis Encapsulated Esophageal Adenocarcinoma Esophageal Intraepithelial Neoplasia Esophagus FDA approved Foundations Funding Future Gastroesophageal reflux disease Genetic Genetic Markers Genomics Goals Guidelines Incidence Individual Investigation Knowledge Large-Scale Sequencing Lead Malignant Neoplasms Metaplasia Molecular Mutate Mutation Mutation Detection Neoadjuvant Therapy Outcome Patient-Focused Outcomes Patients Plasma Porifera Prognosis Prognostic Marker Publishing Recommendation Recurrence Resources Risk Sampling Sensitivity and Specificity Somatic Mutation Specificity Specimen Staging Surveillance Program Survival Rate Testing Time Tissue Sample United States Work base cancer diagnosis cell free DNA chemoradiation chemotherapy clinical biomarkers clinical development comparative data resource detection test effectiveness evaluation exome sequencing genetic signature genome sequencing genomic signature high risk improved innovation multidisciplinary mutant neoplastic next generation sequencing novel novel strategies patient subsets prognostic prognostic assays prognostic value screening success targeted sequencing theories tissue resource transcriptome sequencing tumor tumor DNA tumor diagnosis whole genome

项目摘要

Abstract. The primary goal of this proposal is to develop novel molecular approaches for early detection of esophageal adenocarcinoma (EAC). EAC arises in the setting of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE); a metaplastic change resulting from GERD. This knowledge has driven endoscopic screening and surveillance recommendations for individuals with GERD and BE but compliance is low and the vast majority of new EAC cases are still diagnosed at late stage, when the tumor is inoperable and prognosis is extremely poor. Over the past 6-8 years, we have developed a highly collaborative, multi-institutional and multi- disciplinary team focused on the development of clinically useful biomarkers for EAC. This proposal will build on our previously funded projects and the clinical and technical resources available to us through these studies, in order to evaluate two different approaches to early detection of EAC. The first approach is based on detection of somatic mutation and DNA copy number abnormality signatures in esophageal cytology samples. Published studies and our own ongoing work strongly indicate that accumulation of somatic mutations and major chromosomal rearrangements drive the progression from BE to EAC. We believe that these changes can be leveraged to identify a genomic signature for progression that can be detected in cytology samples using a targeted next-generation sequencing (NGS) test. Identification of the genomic signature is ongoing in our group through large-scale comparative sequencing of EAC and pre-neoplastic tissue samples. To evaluate the effectiveness of this signature in identifying progression, we are currently collecting ~350 esophageal cytology samples using an encapsulated sponge called the EsophaCap™. This device is not yet commercially available, but has been provided to us under arrangement with CapNostics LLC and is currently approved for investigational testing in the USA and Canada. These unique data and tissue resources will be used in Specific Aim 1 to evaluate the sensitivity and specificity of a targeted NGS analysis of esophageal cytology samples to detect dysplasia and early EAC. The second approach also leverages our large-scale sequencing data and targeted sequencing assays, but in this case we will evaluate the detection of mutations in circulating, cell-free DNA isolated from plasma as a biomarker for EAC. We are currently collecting plasma from all patients who swallow the EsophaCap™ device and this provides an excellent tissue resource in which to test detection of circulating tumor DNA (ctDNA). To aid in the detection of ctDNA, we have developed an ultra-sensitive NGS- based assay that can detect mutations at multiple loci with sensitivity as low as 0.05% (1/2000) mutant allele fraction. These resources will be used in Specific Aim 2 in order to evaluate the sensitivity and specificity of ctDNA for detection of stage I and II EAC. Finally, studies indicate that ctDNA detection may have prognostic value. In Specific Aim 3 we will evaluate the prognostic value of ctDNA in stage I and II EAC patients with the hope that this may prove useful for directing neoadjuvant therapy in these patients.

抽象的。该提案的主要目标是开发新的分子方法用于早期检测食管腺癌（EAC）。EAC出现在胃食管反流病（GERD）的背景下， Barrett食管（BE）; GERD导致的化生性变化。这一知识推动了内窥镜对GERD和BE患者的筛查和监测建议，但依从性较低，绝大多数新的EAC病例仍在晚期诊断，此时肿瘤不可手术，预后不佳。极其贫穷。在过去的6-8年里，我们已经建立了一个高度合作，多机构和多一个学科团队专注于开发临床上有用的EAC生物标志物。该提案将建立我们以前资助的项目和临床和技术资源，我们通过这些研究，以评估早期检测EAC的两种不同方法。第一种方法基于食管细胞学样本中体细胞突变和DNA拷贝数异常标记的检测。已发表的研究和我们自己正在进行的工作强烈表明，体细胞突变的积累和主要的染色体重排驱动从BE到EAC的进展。我们相信这些变化可用于鉴定可在细胞学样品中检测到的进展的基因组标记使用靶向下一代测序（NGS）测试。基因组签名的鉴定正在进行中，我们的小组通过EAC和癌前组织样本的大规模比较测序。评价该特征在识别进展方面的有效性，我们目前收集了约350例食管癌患者，使用称为EsophaCap™的包封海绵对细胞学样品进行细胞学分析。该设备尚未商业化。可用，但已根据与CapNostics LLC的安排提供给我们，目前已批准用于在美国和加拿大进行研究性测试。这些独特的数据和组织资源将用于特定的目的1评价食管细胞学样本靶向NGS分析的敏感性和特异性，检测发育不良和早期EAC。第二种方法也利用了我们的大规模测序数据，靶向测序检测，但在这种情况下，我们将评估检测循环，无细胞，从血浆中分离的DNA作为EAC的生物标志物。我们目前正在收集所有患者的血浆，吞咽EsophaCap™装置，这提供了极好的组织资源，在其中测试循环肿瘤DNA（ctDNA）。为了帮助检测ctDNA，我们开发了一种超灵敏的NGS- 一种可检测多个基因座突变的检测方法，灵敏度低至0.05%（1/2000）突变等位基因分数这些资源将用于特定目标2，以评价以下方面的敏感性和特异性：用于检测I期和II期EAC的ctDNA。最后，研究表明ctDNA检测可能具有预后值在具体目标3中，我们将评估ctDNA在I期和II期EAC患者中的预后价值，希望这可以证明对指导这些患者的新辅助治疗有用。