Methylation in Cancer Progression of Barrett's Esophagus

巴雷特食管癌症进展中的甲基化

• 批准号: 7098419
• 负责人: JEAN S WANG
• 金额: $ 13.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098419
• 关键词: Barretts esophagus; DNA methylation; adenocarcinoma; biomarker; cancer risk; clinical research; early diagnosis; human subject; immunocytochemistry; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic transformation; p53 gene /protein; patient oriented research; polymerase chain reaction; preneoplastic state; tissue /cell preparation

DESCRIPTION (provided by applicant): Dr. Jean Wang is an Instructor of Medicine in the Division of Gastroenterology at the Johns Hopkins University School of Medicine and a Ph.D. student in the Graduate Training Program in Clinical Investigation, a joint program sponsored by the Johns Hopkins Schools of Public Health and Medicine. Her immediate career goals are to complete and publish her Ph.D. thesis work in Clinical Investigation and to establish a career in clinical investigation. Dr. Wang's long-term career goals are to become an independent clinical investigator in gastrointestinal oncology with expertise in patient-oriented research involving genetic epidemiology, outcomes, and prevention. This award will enable her to acquire the skills to become a leader in clinical investigation under the guidance of her mentors and through additional coursework in genetic epidemiology, bioinformatics, and clinical research study design. Patients with Barrett's esophagus (BE) have an increased risk of esophageal adenocarcinoma that is 40-125 times higher than in the general population. However, there are currently no reliable predictors of neoplastic progression. DMA hypermethylation is an epigenetic phenomenon that holds great promise as a molecular marker for early detection of cancer. We hypothesize that DNA hypermethylation will predict which patients with BE are likely to progress to adenocarcinoma. We propose the following specific aims utilizing a panel of 8 cancer-related genes (p16, E-cadherin, APC, ER, MGMT, DARK, RAR-beta and TIMP3): 1) To compare the prevalence of gene hypermethylation in BE patients with different grades of dysplasia and/or adenocarcinoma; 2) To determine whether the presence of gene hypermethylation in initial biopsies of BE patients is associated with progression to adenocarcinoma, and to compare gene hypermethylation with currently available markers for neoplastic progression; and 3) To determine whether methylated DNA from BE and/or adenocarcinoma can be detected in the peripheral blood of patients, by comparing methylation profiles of esophageal biopsy specimens with peripheral blood samples taken at the same time. Using these specific aims, we will compare the utility of DNA hypermethylation with current markers for neoplastic progression (detection of dysplasia and p53 immunohistochemical staining). Our long-term goal is to determine whether DNA hypermethylation can identify BE patients who are at high risk for neoplastic progression, thus allowing for early intervention and preventive measures. This research is of significant relevance to public health because the incidence of esophageal adenocarcinoma in the U.S. has increased more than 300% in the past 40 years and BE is considered to be the primary risk factor for esophageal adenocarcinoma.

描述（由申请人提供）： Jean Wang博士是约翰·霍普金斯大学医学院胃肠病学系医学教练和博士学位。 Johns Hopkins公共卫生和医学学校赞助的临床研究研究生培训计划的学生。她的直接职业目标是填写和出版她的博士学位。论文在临床研究中的工作并在临床研究中建立职业。 Wang博士的长期职业目标是成为胃肠道肿瘤学的独立临床研究者，在涉及遗传流行病学，结局和预防的患者研究方面具有专业知识。该奖项将使她能够在导师的指导下以及通过遗传流行病学，生物信息学和临床研究设计设计的其他课程来获得临床研究的技能。 巴雷特食管（BE）患者患食道腺癌的风险增加，比普通人群高40-125倍。但是，目前尚无肿瘤进展的可靠预测指标。 DMA高甲基化是一种表观遗传现象，它是早期检测癌症的分子标记的巨大希望。我们假设DNA高甲基化将预测哪些患者可能会发展为腺癌。我们提出了以下特定目的，利用一组与癌症相关的基因（P16，E-钙粘蛋白，APC，ER，MGMT，MGMT，Dark，rar-beta和timp3）：1）比较患有BE患者的基因高甲基化患病率不同等级的发育不良和/或腺癌； 2）确定在BE患者的初始活检中的基因高甲基化是否与腺癌的进展有关，并将基因高甲基化与当前可用的肿瘤进展标记进行比较； 3）通过将食管活检标本的甲基化谱与同时服用的外周血样本进行比较，可以在患者的外周血中检测到来自BE和/或腺癌的甲基化DNA。 使用这些特定目的，我们将比较DNA高甲基化的实用性与当前标记物用于肿瘤进展（检测发育异常和p53免疫组织化学染色）。我们的长期目标是确定DNA高甲基化是否可以识别出有肿瘤进展的高风险的患者，从而可以进行早期干预和预防措施。 这项研究与公共卫生具有很大相关性，因为在过去40年中，美国食管腺癌的发生率增长了300％以上，被认为是食管腺癌的主要危险因素。