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: 7633166
• 负责人: JEAN S WANG
• 金额: $ 2.59万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633166
• 关键词: Adenocarcinoma; Archives; Award; Barrett Esophagus; Bioinformatics; Biological Markers; Biopsy; Biopsy Specimen; Blood specimen; CDKN2A gene; Chemoprevention; Clinical Investigator; Clinical Research; Clinical Trials; DNA; Detection; Doctor of Philosophy; Dysplasia; E-Cadherin; Early treatment; Endoscopic Biopsy; Endoscopy; Enrollment; Epigenetic Process; Esophageal; Esophageal Adenocarcinoma; Event; Gastroenterology; Gene Expression; General Population; Genes; Genetic; Goals; Histologic; Hospitals; Hypermethylation; Incidence; Joints; MGMT gene; Malignant Neoplasms; Measures; Medicine; Mentors; Methods; Methylation; Neoplastic Cell Transformation; Operative Surgical Procedures; Outcome; Pathologic; Patients; Prevalence; Prevention; Preventive; Promoter Regions; Public Health; Public Health Schools; Publishing; Research; Research Design; Research Personnel; Risk; Risk Factors; Screening for cancer; Specimen; Staging; Staining method; Stains; Students; TIMP3 gene; TP53 gene; Techniques; Time; Training Programs; Universities; Work; career; cohort; gastrointestinal; genetic epidemiology; high risk; human RARB protein; instructor; medical schools; molecular marker; oncology; patient oriented research; peripheral blood; programs; research study; skills; time use; tumor progression

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的医学讲师，也是约翰·霍普金斯大学医学院的博士学位。临床研究研究生培训项目的学生，这是由约翰·霍普金斯大学公共卫生与医学院赞助的联合项目。她的近期职业目标是完成并出版她的博士学位。论文从事临床研究并建立临床研究职业生涯。王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，在以患者为导向的遗传流行病学、结果和预防研究方面拥有专业知识。该奖项将使她能够在导师的指导下并通过遗传流行病学、生物信息学和临床研究设计方面的额外课程获得成为临床研究领导者的技能。 巴雷特食管 (BE) 患者患食管腺癌的风险比普通人群高 40-125 倍。然而，目前尚无肿瘤进展的可靠预测因子。 DMA 高甲基化是一种表观遗传现象，有望作为癌症早期检测的分子标记。我们假设 DNA 高甲基化将预测哪些 BE 患者可能进展为腺癌。我们利用一组 8 个癌症相关基因（p16、E-钙粘蛋白、APC、ER、MGMT、DARK、RAR-β 和 TIMP3）提出以下具体目标： 1) 比较 BE 患者中基因高甲基化的患病率不同级别的不典型增生和/或腺癌； 2) 确定BE患者初始活检中基因高甲基化是否与腺癌进展相关，并将基因高甲基化与目前可用的肿瘤进展标志物进行比较； 3) 通过比较食管活检标本与同时采集的外周血样本的甲基化谱，确定是否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。 利用这些具体目标，我们将比较 DNA 高甲基化与当前肿瘤进展标志物（异型增生检测和 p53 免疫组织化学染色）的效用。我们的长期目标是确定 DNA 高甲基化是否可以识别肿瘤进展高风险的 BE 患者，从而采取早期干预和预防措施。 这项研究与公共卫生具有重要意义，因为过去40年美国食管腺癌的发病率增加了300%以上，而BE被认为是食管腺癌的主要危险因素。