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：被称为巴雷特食道(BE)的食管肠化被认为是 是对慢性胃酸和胆汁反流的反应，具有重要的临床意义，因为它是 食管腺癌的前驱症状(EAC)。BE的发病率相当高，估计发现于 至少1：100人。虽然进展到癌症的人相对较少，但能够 检测和治疗那些有进展风险的人，因为EAC是一种具有早期扩散潜力的侵袭性癌症。 到目前为止，在BE患者中筛查高危疾病的努力并不是非常成功。因此， 迫切需要确定BE进展为EAC的过程，开发生物标记物以 诊断BE组织的早期进展并评估进展风险，以及开发新的治疗方法 治疗。R01提案的目标是调查生物标记物识别BE患者的能力。 进展的风险很高。利用两项外部资助的非发育不良BE基因组研究结果 (NDBE)和BE与低度不典型增生(LGD)和之前发表的结果，我们将比较生物标记物 并在两个前瞻性队列中确定风险分层的优化组合，包括 NDBE或LGD。然后，我们将在一个独立的美国队列中验证我们的风险分层分析。最后，我们会 在配对的活检和刷检样本中比较我们的基因组生物标记物小组结果。独一无二的协作 在派Stachler博士、胃肠病专家(J Bergman博士)、才华横溢的计算生物学家(Dr. CZ Zhang)和一位专家生物统计学家(K Zwinderman博士)以及主要合作者允许真正的 要进行的创新研究。这将使用史无前例的临床集合来完成 衍生样本，高度优化的定向测序面板，以及新的计算方法， 允许在具有成本效益、临床相关的庄园中确定广泛的信息。 目标1：确定一组基因组生物标记物，高度预测恶性黑色素瘤的活检进展 诊断为NDBE和LGD的患者的前瞻性队列，并评估是否增加 基于甲基化的生物标记物改善了层积。对于临床实施，所有生物标记物都应该 进行头对头比较，以确定用于风险分层的最佳生物标记物组合。 目标2：在具有基线的多机构患者队列中验证风险分层分析 诊断为NDBE或LGD。对于临床实施，验证任何风险分层分析都至关重要。 关注临床相关时间点的完全独立的队列。 目标3：确定基于刷子的采样设备是否改进了标准的生物标记物检测 内窥镜活检。对BE上皮进行广泛采样可能会提高BE上皮细胞的检测率 基因组或甲基化生物标记物，因此我们将确定来自刷牙设备的样本是否可以 与标准活组织检查相比，更好地对患者进行风险分层。