Optimization and validation of a biomarker panel for risk stratification in Barrett's esophagus

用于巴雷特食管风险分层的生物标志物组的优化和验证

• 批准号: 10584271
• 负责人: Matthew D Stachler
• 金额: $ 64.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-28 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584271
• 关键词: American; Aneuploidy; Area; Barrett Esophagus; Benign; Bile Reflux; Biological Assay; Biological Markers; Biometry; Biopsy; Case/Control Studies; Chronic; Clinical; Clinical Management; Collaborations; Collection; Computational Biology; Computational Technique; Coupled; Credentialing; DNA Sequence Alteration; Detection; Development; Devices; Diagnosis; Disease; Dysplasia; Early Diagnosis; Endoscopic Biopsy; Endoscopy; Epithelium; Esophageal Adenocarcinoma; Esophageal Tissue; Esophagus; Evaluation; Functional disorder; Funding; Gastroenterologist; Gastroenterology; Gastroesophageal reflux disease; Genome; Genomics; Goals; Head; High Prevalence; Histologic; Incidence; Institution; Intestines; Left; Lesion; Malignant Neoplasms; Malignant neoplasm of esophagus; Methylation; Modeling; Mutation; Mutation Detection; Outcome; Pathology; Patients; Persons; Ploidies; Positioning Attribute; Precancerous Conditions; Procedures; Process; Progress Reports; Prospective cohort; Publishing; Recommendation; Research; Resources; Risk; Sampling; Side; Stratification; Structure; TP53 gene; Talents; Testing; Time; Tissue Banks; Tissue Sample; Tissues; Validation; advanced disease; biomarker identification; biomarker panel; cancer genomics; clinical implementation; clinically relevant; clinically significant; cohort; cost; cost effective; disorder risk; epigenomics; genomic biomarker; high risk; improved; innovation; methylation biomarker; novel; novel therapeutics; patient population; patient stratification; predictive marker; premalignant; prevent; progression risk; response; risk stratification; screening; subclonal heterogeneity; surveillance strategy; targeted sequencing; tool

PROJECT SUMMARY: Intestinalization of the esophagus, termed Barrett’s esophagus (BE), is thought to develop in response to chronic acid and bile reflux and carries great clinical significance because it is the precursor to esophageal adenocarcinoma (EAC). The incidence of BE is quite high, estimated to be found in at least 1:100 people. While relatively few with BE progress to cancer there is great importance to being able to detect and treat those at risk of progression as EAC is an aggressive cancer with potential for early spread. Efforts to screen for high-risk disease in those with BE have, to date, not been very successful. Therefore, there is profound need to define the process by which BE progresses into EAC, to develop biomarkers to diagnose early progression and assess progression risk in BE tissues as well as to develop novel therapies for treatment. The objective of this R01 proposal is to investigate the ability of biomarkers to identify BE patients at high risk of progression. Using results from two externally funded genomic studies in non-dysplastic BE (NDBE) and BE with low-grade dysplasia (LGD) and previously published results, we will compare biomarkers and determine an optimized combination for risk stratification in two prospective cohorts including patients with NDBE or LGD. We will then validate our risk stratification assay in an independent US cohort. Finally, we will compare our genomic biomarker panel results in paired biopsy and brush samples. A unique collaboration between the PI Dr. Stachler, expert gastroenterologist (Dr. J Bergman), a talented computational biologist (Dr. CZ Zhang), and an expert biostatistician (Dr. K Zwinderman) along with key collaborators allows a truly innovated study to be performed. This will be accomplished using an unprecedented collection of clinically derived samples, a highly optimized targeted sequencing panel, and novel computational approaches that allow a wide array of information to be determined in a cost effective, clinically relevant manor. Aim 1: Identify a set of genomic biomarkers highly predictive of progression in biopsies from a prospective cohort of patients diagnosed with NDBE and LGD and assess whether the addition of methylation-based biomarkers improves stratification. For clinical implementation all biomarkers should be compared head to head in order to determine an optimized combination of biomarkers for risk stratification. Aim 2: Validate the risk stratification assay in a multi-institutional cohort of patients with a baseline diagnosis of NDBE or LGD. For clinical implementation, it is vital to validate any risk stratification assay on completely independent cohorts looking at clinically relevant time points. Aim 3: Determine if brush-based sampling devices improve biomarker detection over standard endoscopic biopsies. Broad sampling of the BE epithelium may allow for increased rates of detection for genomic or methylation biomarkers, therefore we will determine if samples from a brushed based device can better risk stratify patients compared to standard biopsies.

项目摘要：被认为是巴雷特食管（BE）的食道的肠道化。 响应于慢性酸和胆汁反射的响应并具有极大的临床意义，因为它是 食管腺癌（EAC）的前体。 BE的事件很高，估计在AT 至少1：100人。虽然相对较少的癌症进展，但能够 检测和治疗有进展风险的人是一种侵略性癌症，具有早期蔓延的潜力。 迄今为止，在患有BE的患者中筛查高风险疾病的努力并不是很成功。所以， 非常需要定义进入EAC的过程，以开发生物标志物 诊断是组织中的早期进展和评估进展风险，以及开发新的疗法 治疗。该R01提案的目的是调查生物标志物鉴定为患者的能力 高风险的进展风险。利用来自非外部基因组研究的非塑性基因组研究的结果 （NDBE）并患有低度发育异常（LGD），并以前发表的结果，我们将比较生物标志物 并确定两个前瞻性队列中风险分层的优化组合，包括 NDBE或LGD。然后，我们将在美国独立队列中验证我们的风险分层测定法。最后，我们会的 比较我们的基因组生物标志物面板会产生成对的活检和刷样品。独特的合作 在PI博士Stachler博士之间，专家胃肠病学家（J Bergman博士），才华横溢的计算生物学家（博士 CZ Zhang）和专业的生物统计学家（K Zwinderman博士）以及主要的合作者允许真正的合作者 进行创新的研究要进行。这将是使用前所未有的临床集合来完成的 派生样品，一个高度优化的目标测序面板以及新颖的计算方法 允许通过具有成本效益，临床相关的庄园来确定各种各样的信息。 目标1：确定一组基因组生物标志物高度预测活检中的进展 诊断为NDBE和LGD的患者的预期队列以及评估是否添加 基于甲基化的生物标志物改善了分层。对于临床实施，所有生物标志物都应 比较头到头，以确定生物标志物的优化组合以进行风险分层。 目标2：验证基线多机构队列中的风险分层测定法 诊断NDBE或LGD。对于临床实施，至关重要的是验证任何风险分层测定法 完全独立的人群查看临床相关时间点。 AIM 3：确定基于刷子的采样设备是否改善了标准生物标志物检测 内窥镜活检。 Be上皮的广泛采样可能允许提高检测率 基因组或甲基化生物标志物，因此我们将确定来自基于拉丝设备的样品是否可以 与标准活检相比，更好的风险将患者分层。