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.

项目总结：食管的肠化，称为巴雷特食管（BE），被认为是 慢性酸和胆汁反流的反应，并进行重大的临床意义，因为它是 食管腺癌（EAC）的前体。BE的发病率相当高，估计在 1：100人。虽然相对较少的BE进展为癌症，但能够 检测和治疗有进展风险的患者，因为EAC是一种具有早期扩散潜力的侵袭性癌症。 迄今为止，在BE患者中筛查高危疾病的努力并不十分成功。因此，我们认为， 我们迫切需要确定BE进展为EAC的过程，开发生物标志物， 诊断早期进展并评估BE组织中的进展风险，以及开发新的治疗方法， 治疗本R01提案的目的是研究生物标志物识别BE患者的能力， 进展的高风险。使用两项外部资助的非异型增生BE基因组研究的结果 （NDBE）和BE伴低度异型增生（LGD）和以前发表的结果，我们将比较生物标志物 并在两个前瞻性队列中确定风险分层的最佳组合， 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。最后我们将 比较配对活检和刷检样本中的基因组生物标志物面板结果。的独特合作 之间的PI博士Stachler，专家胃肠病学家（博士J伯格曼），一个有才华的计算生物学家（博士。 CZ Zhang）和生物统计学专家（K Zwinderman博士）沿着主要合作者， 进行创新研究。这将通过前所未有的临床收集来实现。 衍生的样品，高度优化的靶向测序面板，和新的计算方法， 允许以成本有效的、临床相关的方式确定广泛的信息。 目的1：确定一组高度预测来自非小细胞肺癌的活检进展的基因组生物标志物。 诊断为NDBE和LGD的患者的前瞻性队列，并评估是否添加 基于甲基化的生物标志物改善了分层。对于临床实施，所有生物标志物应 头对头比较，以确定用于风险分层的生物标志物的优化组合。 目的2：在多机构队列患者中进行风险分层分析， 诊断NDBE或LGD。对于临床实施，验证任何风险分层分析至关重要， 观察临床相关时间点的完全独立队列。 目标3：确定基于刷子的采样设备是否能提高生物标志物检测的标准 内窥镜活检BE上皮细胞的广泛采样可以提高BE的检出率。 基因组或甲基化生物标志物，因此，我们将确定来自刷基器械的样本是否可以 与标准活检相比，更好地对患者进行风险分层。