Predictors of Progression from Barrett's Esophagus to esophageal adenocarcinoma

从巴雷特食管进展为食管腺癌的预测因子

• 批准号: 7819331
• 负责人: BRIAN J REID
• 金额: $ 49.88万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7819331
• 关键词: Ablation; Alcohol consumption; Aspirin; Barrett Esophagus; Biological; Biological Assay; Biology; Biometry; Biopsy; Cancer Surveillance Research Program; Categories; Cells; Chromosomal Instability; Chromosome abnormality; Chromosomes; Clinical; Clinical Management; Clinical Research; Clonal Evolution; Cohort Studies; Colorectal; Complex; Computational Biology; DNA; Data; Data Set; Development; Diagnostic; Diet; Dimensions; Early Diagnosis; Endoscopy; Environmental Risk Factor; Epidemiology; Epithelium; Esophageal Adenocarcinoma; Esophagus; Event; Evolution; Exposure to; Family Cancer History; Future; Gastroesophageal reflux disease; Genome; Genomic Instability; Genomics; Goals; Hip region structure; Human; Incidence; Individual; Intervention; Intraepithelial Neoplasia; Laboratories; Lead; Length; Life Style; Loss of Heterozygosity; Maintenance; Malignant Neoplasms; Measures; Methods; Molecular; Molecular Biology; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Outcome; Participant; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Population; Recording of previous events; Relative (related person); Research; Research Design; Resolution; Risk; Risk Factors; Sampling Studies; Stratification; Symptoms; Technology; Testing; Time; Tissues; Tobacco use; Translational Research; United States; Validation; cancer prevention; case control; cohort; density; design; experience; follow-up; genome-wide; health care delivery; improved; in vivo; in vivo Model; modifiable risk; mortality; multidisciplinary; neoplastic; novel; prevent; primary outcome; public health relevance; time use; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): This Challenge Application is directly and completely responsive to Specific Challenge Topic: 03-CA-102 "Biologic Predictors of Progression in Barrett's Esophagus". It comes from a research team with more than two decades of experience investigating Barrett's esophagus (BE), the only established precursor to esophageal adenocarcinoma (EA), a highly lethal malignancy whose incidence has increased more than 600% in three decades. The hypothesis that clonal evolution underlies neoplastic progression has been well accepted for 30 years, but the temporal course of genomic changes during evolution to cancer has rarely been studied in humans in vivo. BE is a unique in vivo model of human intraepithelial neoplasia, and the Seattle BE cohort is one of the largest and best characterized in the world. Our multidisciplinary team encompasses expertise in clinical research, genomics, evolutionary biology, molecular biology, computational biology, epidemiology and biostatistics, including the analysis of complex datasets. Using a nested cohort sampling study design drawing from the above cohort of 456 individuals with BE, of whom 77 already have progressed to EA, we will evaluate the following hypotheses: (1) high-resolution assessment of somatic genomic abnormalities (SGA) using a molecular cytogenomic 2.7 million SNP/probe array can identify novel regions of chromosome abnormalities that can be assessed as biological predictors of progression from BE to EA (Aim 1); (2) the rate of evolution of SGA over time, which we term somatic genomic instability (SGI), will differentiate between persons at high and low risk of developing EA (Aim 2); and (3) SGI and its effect on risk of EA are modulated by key host and environmental risk and protective factors (Aim 3). Our translational research goals are to improve (1) risk stratification for BE progression to EA at the baseline endoscopy using a diagnostic array that can be readily implemented in clinical laboratories, (2) efficiency of endoscopic surveillance for early detection of EA using measures of genomic instability (SGI) that distinguish individuals who will and will not progress to EA, and (3) clinical management of BE by identifying mechanisms by which risk and protective factors modulate progression that lead to non-invasive interventions, including lifestyle changes, to reduce the incidence and mortality of EA. PUBLIC HEALTH RELEVANCE: Barrett's esophagus is the only known precursor to esophageal adenocarcinoma, a highly lethal cancer that has been increasing at an alarming rate in the United States, but most people with Barrett's esophagus remain free from cancer throughout their lifetimes. We will study the evolution of abnormalities in Barrett's esophagus that predict progression to cancer as well as how diet, the use of common drugs like aspirin, and other lifestyle choices can change the likelihood of developing this cancer. This will improve health care delivery by focusing cancer prevention and early detection efforts on those people most likely to benefit, while reassuring individuals at low risk and preventing exposure to invasive, potentially toxic interventions from which they have little chance of benefit.

描述（由申请人提供）：此挑战申请直接且完全响应特定挑战主题：03-CA-102“ Barrett食管中进展的生物学预测指标”。它来自一个研究团队，该研究团队具有研究Barrett食管（BE）的经验，这是食管腺癌（EA）唯一建立的前体，这是一种高度致命的恶性肿瘤，其发病率在三十年中增加了600％。克隆进化构成肿瘤进展的基础已有30年的假设已被良好接受，但是在体内的人类中，很少研究为癌症进化过程中基因组变化的时间变化。 BE是人类上皮内肿瘤的独特体内模型，西雅图BE COHORT是世界上最大，最佳的特征之一。我们的多学科团队包括临床研究，基因组学，进化生物学，分子生物学，计算生物学，流行病学和生物统计学的专业知识，包括对复杂数据集的分析。 Using a nested cohort sampling study design drawing from the above cohort of 456 individuals with BE, of whom 77 already have progressed to EA, we will evaluate the following hypotheses: (1) high-resolution assessment of somatic genomic abnormalities (SGA) using a molecular cytogenomic 2.7 million SNP/probe array can identify novel regions of chromosome abnormalities that can be assessed as biological predictors从BE到EA的发展（AIM 1）； （2）SGA随时间的进化率（我们称为体细胞基因组不稳定性（SGI））将区分出高和低风险发展EA的人（AIM 2）； （3）SGI及其对EA风险的影响受到关键宿主和环境风险和保护因素的调节（AIM 3）。我们的翻译研究目标是改善（1）使用诊断阵列在基线内窥镜检查处的风险分层，可以在临床实验室中很容易实施，（2）内窥镜监测的效率，通过将EA的衡量基因组不稳定性（SGI）降级为临床的人（SGI）进行临床的机构（SGI和3）的效率（3），并且（3调节导致非侵入性干预措施（包括生活方式改变）的进展，以降低EA的发病率和死亡率。 公共卫生相关性：巴雷特的食管是食管腺癌的唯一已知的先驱，这是一种高度致命的癌症，在美国的速度一直以惊人的速度增加，但大多数患有巴雷特食管的人在整个生命中仍然没有癌症。我们将研究Barrett食管异常的演变，这些异常预测癌症的发展以及饮食，使用阿司匹林等常见药物以及其他生活方式选择的方式如何改变发展这种癌症的可能性。这将通过将预防癌症的预防和早期发现工作集中在最有可能受益的人中，同时使风险较低的人放心，并防止暴露于侵入性的，潜在的有毒干预措施，从而改善医疗保健的交付。