Barrett's Esophagus: Predictors of Progression

巴雷特食管：进展的预测因素

• 批准号: 8929158
• 负责人: BRIAN J REID
• 金额: $ 246.28万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-16 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929158
• 关键词: Ablation; Advanced Malignant Neoplasm; Barrett Esophagus; Biological Process; Biology; Breast; Caring; Cell Lineage; Cells; Chromosomal Instability; Cohort Studies; Colon; DNA Sequence Alteration; Detection; Diagnosis; Disease; Early Diagnosis; Elements; Environmental Risk Factor; Esophageal Adenocarcinoma; Evolution; Frequencies; Funding; Generations; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Incidence; Individual; Integration Host Factors; Lead; Length; Lung; Malignant Neoplasms; Methods; Modeling; Mutation; Organ; Outcome; Ovary; Patients; Phylogenetic Analysis; Population; Prevention; Prevention strategy; Primary Health Care; Process; Research; Risk; Screening for cancer; Somatic Mutation; Time; United States; Variant; base; cancer cell; design; genome wide association study; improved; mortality; neoplastic; neoplastic cell; response; screening; surveillance strategy; tool; treatment strategy

DESCRIPTION (provided by applicant): Cancer is a disease of somatic genomic evolution; and all cancers are believed to arise as a result of somatic genomic instability, generation of mutations and evolution of neoplastic cell lineages that lead to cancer. The incidence and mortality of esophageal adenocarcinoma (EA) have been increasing more rapidly than any other cancer in the United States for the past four decades. Barrett's esophagus (BE) is the only known precursor to EA. However, current screening strategies selectively detect slowly or non-progressing BE that does not progress to EA over a lifetime ("over diagnosis"). In contrast, most EA arise in patients without a prior diagnosis of BE even though the evidence indicates that BE was present but undiagnosed ("under diagnosis"). Over- and under diagnosis are believed to due to length bias in which screening misses rapidly progressive BE while selectively detecting slowly progressive BE. However, almost nothing is known about the biology underlying length bias. During the current funding period, in a longitudinal case-cohort study, we made transformative advances in defining the biology underlying rapid and slowly or non-progressive BE. We found that rapidly progressive BE was characterized by chromosome instability and a four year window of opportunity for early detection of EA whereas BE that did not progress to EA largely maintained somatic genome stability over prolonged periods. We will build on these transformative advances. Our P01 is designed to impact all levels of care from population screening to specialized treatment of patients with BE. Project 1 will determine mutation frequencies at two time points that are associated with progression to EA to improve our understanding of somatic genome dynamics that govern progression and extend the window of opportunity for early detection of cancer. Project 3 will use phylogenetic methods, which look backwards in time, to infer the ancestral lineages of BE in individuals who do and do not progress to EA as well as in individuals pre- and post-endoscopic therapy. This will allow us to identify ancestral lineages that occur early during this evolutionary process that can be used for early detection of EA and improve outcomes of endoscopic therapy. Project 2 will build risk models (1) incorporating GWAS and SGA at two time points, (2) determining relationships among host and environmental factors, and constitutive and somatic genomic alterations pre- and post-endoscopic therapy to predict response to therapy, and (3) incorporate these findings into a comprehensive model to inform (1) screening, (2) surveillance, (3) prevention and (4) endoscopic therapy. RELEVANCE: Most individuals with BE never develop EA, but undergo routine cancer surveillance indefinitely. Successful completion of our research will have a profound impact on screening, surveillance, prevention and treatment strategies for BE/EA. It will also have a profound impact on our understanding of the rate of mutations that transforms a BE cell to a cancer cell, which will be applicable to most cancers, including breast, ovary, lung and colon, which are more difficult to study overtime in the same individual.

描述（由申请人提供）：癌症是一种体细胞基因组进化的疾病；并且人们认为所有癌症都是由于体细胞基因组不稳定性，突变的产生和导致癌症的肿瘤细胞谱系的进化而引起的。在过去的四十年中，食管腺癌（EA）的发病率和死亡率比美国的任何其他癌症都更快。巴雷特的食道（BE）是唯一已知的EA前体。但是，当前的筛查策略选择性地检测到缓慢或未进行的筛查策略在一生中不会发展为EA（“过度诊断”）。相比之下，即使证据表明存在但未被诊断的患者，大多数EA是出现的。据信，过度和诊断的诊断是由于长度偏差，在这种偏见中，筛查会迅速进行，同时选择性地检测到缓慢进行性的BE。但是，几乎一无所知。在当前的资金期间，在一项纵向病例研究中，我们在定义生物学快速，缓慢或非促进的生物学方面取得了变革性的进步。我们发现，快速进步的特征是染色体不稳定性和为EA的早期发现的四年机会之窗，而在长期内，EA并未进行EA的发展。我们将以这些变革性的进步为基础。我们的P01旨在影响从人口筛查到对BE患者的专门治疗的所有水平的护理。项目1将在两个时间点确定与EA的进展相关的突变频率，以提高我们对控制进展的体细胞基因组动力学的理解，并扩大了早期检测的机会窗口。项目3将使用系统发育方法，这些方法会及时向后看，以推断出在ea和范围内和范围后镜像疗法前和个人前进和不发展EA的个人中的祖先谱系。这将使我们能够鉴定出在这种进化过程中早期发生的祖先谱系，该谱系可用于早期检测EA并改善内窥镜治疗的预后。项目2将建立风险模型（1）在两个时间点结合GWA和SGA，（2）确定主机之间的关系 环境因素以及构成和体细胞基因组改变前和后镜面治疗以预测对治疗的反应，以及（3）将这些发现纳入一个综合模型，以告知（1）筛查，（2）监测，（3）预防和（4）内窥镜治疗。 相关性：大多数患有EA永远不会发展的人，但是会无限期地接受常规的癌症监测。成功完成我们的研究将对BE/EA的筛查，监视，预防和治疗策略产生深远的影响。这也将对我们对将BE细胞转变为癌细胞的突变速率的理解产生深远的影响，该突变率将适用于大多数癌症，包括乳腺癌，卵巢，肺和结肠，在同一个体中更难加班。