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：食管肠化，称为巴雷特食管（BE），被认为是一种