Feasibility of Molecular Cytology for the Management of Barrett's Esophagus
分子细胞学治疗巴雷特食管的可行性
基本信息
- 批准号:8880446
- 负责人:
- 金额:$ 21.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-21 至 2017-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAdultAdvanced Malignant NeoplasmAllelesBarrett EsophagusBasal CellBiopsyBiopsy SpecimenCanadaCellsChronicClonal EvolutionColumnar MetaplasiaCountryCytologyDataDevelopmentDevicesDiagnosisDiseaseDisease ProgressionDysplasiaDysplasia in Barrett&aposs EsophagusEarly DiagnosisEndoscopyEpitheliumEsophagealEsophageal AdenocarcinomaEsophagectomyEvolutionExcisionFDA approvedFundingGastroesophageal reflux diseaseGenesGeneticGenomeGlandGoalsGuidelinesHealthHeterogeneityHospitalsIncidenceIndividualLeadMalignant NeoplasmsMetaplasiaModelingMolecularMorbidity - disease rateMutationMutation DetectionNatureNormal CellOutcomePatientsPhysicians&apos OfficesPopulationPositioning AttributePrimary Care PhysicianProceduresPublishingRadiationRecommendationReportingRiskRisk FactorsSamplingSignal TransductionSpecimenSquamous EpitheliumStagingStem cellsSurveillance ProgramSurvival RateTechnologyTestingTissuesVisitWorkbasecancer riskchemotherapycostcost effectiveeffective therapyexome sequencingfollow-upimprovedinsightmortalitymutantnext generation sequencingnoveloutcome forecastsample collectionscreeningtargeted sequencingtranscriptome sequencingtumor
项目摘要
DESCRIPTION (provided by applicant): The incidence of esophageal adenocarcinoma (EAC) has increased dramatically in the US and other Western countries over the past 40 years. EAC is an aggressive tumor that is typically diagnosed at late stage resulting in very poor overall survival. If detected early however, effective treatment options are available including ablation, endoscopic mucosal resection and esophagectomy, with or without chemotherapy and radiation. EAC typically arises in the setting of chronic gastroesophageal reflux disease with the associated development of esophageal columnar metaplasia known as Barrett's Esophagus (BE). BE is the strongest known risk factor for EAC and patients with BE are therefore recommended to enter endoscopic surveillance programs to detect dysplasia or early EAC. However, the use of repeat endoscopies with multiple biopsies is an expensive and invasive model for BE surveillance. We believe that combining esophageal cytology with next-generation sequencing to detect mutations that drive development of dysplasia and EAC will provide a novel, less invasive and more cost-effective approach to BE surveillance. In Specific Aim 1, we will test the feasibility of this hypothesis by combining an FDA approved device for esophageal cytology sample collection (the EsophaCap(tm)) with targeted, next-generation sequencing of a panel of ~100 genes known to be drivers of EAC development. This panel will be identified from whole exome sequence data on 250 EAC samples and RNA-seq data on 100 of the same tumors. This data is available to us through our previously published work (Dulak, et al. Nature Genetics 2013) and an ongoing study funded by Genome Canada. This data, along with access to the EsophaCap(tm) for immediate use in the USA puts us in a unique position to evaluate the feasibility of a molecular cytology test to detect disease progression in patients with BE. Specifically, in Aim 1A we will determine what proportion of EAC driver mutations, identified in multiple biopsy samples, are also detectable in matched cytology samples. This will determine overall feasibility for our proposed approach as the cytology samples will be "contaminated" with normal cells that will dilute the mutant allele fractions. In related aim 1B, we will also determin the mutation heterogeneity in BE by identifying mutations in multiple independent biopsies from the same patients. This will allow us to estimate the sequence depth required to detect all mutations in cytology samples and will also facilitate an analysis of clonal heterogeneity and evolution in BE. Specific Aim 2 will utilize a similar approach to address a critical question regarding ablation of BE; is the neosquamous epithelium that develops following ablation genetically normal or does it harbor mutations that could still incur cancer risk? This will be determined by comparing mutations in BE and neosquamous epithelium pre and post-ablation. This data will help determine the need for follow-up surveillance in BE patients treated with ablative therapy and will provide insight into the origin of stem cells that give rise to BE and neosquamous epithelium.
描述(申请人提供):食管腺癌(EAC)的发病率在过去的40年里在美国和其他西方国家急剧增加。EAC是一种侵袭性肿瘤,通常在晚期诊断,导致总体生存率非常低。然而,如果及早发现,有效的治疗方案包括消融术、内窥镜黏膜切除术和食道切除术,无论是否有化疗和放射治疗。EAC通常发生在慢性胃食道反流病的背景下,伴随着称为Barrett‘s食道(BE)的食管柱状化生的发展。BE是EAC已知的最强危险因素,因此建议BE患者参加内窥镜监测计划,以检测异常增生或早期EAC。然而,使用多次活检的重复内窥镜对于BE监测来说是一种昂贵且有侵入性的模式。我们相信,将食道细胞学与下一代测序相结合来检测导致异型增生和EAC发展的突变将提供一种新的、侵入性更小、更具成本效益的监测方法。在具体目标1中,我们将通过将FDA批准的食道细胞学样本采集设备(EsophaCap(Tm))与对一组约100个已知推动EAC发展的基因进行定向下一代测序相结合,来测试这一假设的可行性。这个小组将从250个EAC样本的整个外显子组序列数据和100个相同肿瘤的RNA-SEQ数据中识别出来。这些数据可以通过我们以前发表的工作(Dulak等人)获得。自然遗传学2013),以及由加拿大基因组公司资助的一项正在进行的研究。这些数据,以及可在美国立即使用的EsophaCap(Tm),使我们处于独特的地位,可以评估分子细胞学测试检测BE患者疾病进展的可行性。具体地说,在目标1A中,我们将确定在多个活检样本中发现的EAC驱动突变在匹配的细胞学样本中也可检测到的比例。这将决定我们提议的方法的总体可行性,因为细胞学样本将被正常细胞“污染”,这些正常细胞将稀释突变的等位基因部分。在相关的目标1B中,我们还将通过鉴定来自同一患者的多个独立活检组织的突变来确定BE的突变异质性。这将使我们能够估计检测细胞学样本中所有突变所需的序列深度,并将有助于分析BE的克隆异质性和进化。特殊目标2将利用类似的方法来解决关于BE消融的一个关键问题:消融后形成的新鳞片上皮在遗传上是正常的,还是它含有仍然可能引发癌症风险的突变?这将通过比较BE和新鳞状上皮在消融前后的突变来确定。这些数据将有助于确定是否需要对接受消融治疗的BE患者进行随访监测,并将提供对形成BE和新鳞片上皮的干细胞来源的洞察。
项目成果
期刊论文数量(0)
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Tony E Godfrey其他文献
Tony E Godfrey的其他文献
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{{ truncateString('Tony E Godfrey', 18)}}的其他基金
Development of diagnostic and prognostic tests for esophageal adenocarcinoma
食管腺癌诊断和预后测试的发展
- 批准号:
10057357 - 财政年份:2016
- 资助金额:
$ 21.44万 - 项目类别:
Development of diagnostic and prognostic tests for esophageal adenocarcinoma
食管腺癌诊断和预后测试的发展
- 批准号:
10308014 - 财政年份:2016
- 资助金额:
$ 21.44万 - 项目类别:
Innovative approach to cancer detection and treatment monitoring
癌症检测和治疗监测的创新方法
- 批准号:
8643777 - 财政年份:2013
- 资助金额:
$ 21.44万 - 项目类别:
Innovative approach to cancer detection and treatment monitoring
癌症检测和治疗监测的创新方法
- 批准号:
8426388 - 财政年份:2013
- 资助金额:
$ 21.44万 - 项目类别:
Impact of Biological, Clinical, and Social Determinants on Trauma and Trauma Outcomes
生物学、临床和社会决定因素对创伤和创伤结果的影响
- 批准号:
10344300 - 财政年份:2010
- 资助金额:
$ 21.44万 - 项目类别:
Impact of Biological, Clinical, and Social Determinants on Trauma and Trauma Outcomes
生物学、临床和社会决定因素对创伤和创伤结果的影响
- 批准号:
10616684 - 财政年份:2010
- 资助金额:
$ 21.44万 - 项目类别:
Biomarkers for Esophageal Cancer Progression and Prognosis
食管癌进展和预后的生物标志物
- 批准号:
7909276 - 财政年份:2009
- 资助金额:
$ 21.44万 - 项目类别:
Biomarkers for Esophageal Cancer Progression and Prognosis
食管癌进展和预后的生物标志物
- 批准号:
7687433 - 财政年份:2008
- 资助金额:
$ 21.44万 - 项目类别:
Biomarkers for Esophageal Cancer Progression and Prognosis
食管癌进展和预后的生物标志物
- 批准号:
7523588 - 财政年份:2008
- 资助金额:
$ 21.44万 - 项目类别:
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