Agarwal Archana, Polineni Rahul, Hussein Zulfiqar, Vigoda Ivette, Bhagat Tushar D, Bhattacharyya Sanchari, Maitra Anirban, Verma Amit
Steward Carney Hospital, Dorchester, MA 02124, USA.
Int J Clin Exp Pathol. 2012;5(5):382-96. Epub 2012 May 23.
Barrett's esophagus, a pre-malignant condition that can lead to esophageal adenocarcinoma, is characterized by histological changes in the normal squamous epithelium of the esophagus. Numerous molecular changes occur during the multistage conversion of Barrett's metaplasia to dysplasia and frank adenocarcinoma. Epigenetic changes, especially changes in DNA methylation are widespread during this process. Aberrant DNA methylation has been shown to occur at promoters of tumor suppressor genes, adhesion molecules and DNA repair genes during Barrett's esophagus. These epigenetic alterations can be used as molecular biomarkers for risk stratification and early detection of esophageal adenocarcinoma. We also show that genome wide analysis of methylation surprisingly reveals that global hypomethylation and not hypermethylation is the dominant change during Barrett's metaplasia. The transformation of Barrett's esophagus to frank adenocarcinoma is in turn characterized by much smaller wave of selective promoter hypermethylation. These studies reveal many novel, potential targets for new therapies and illustrate the utility of incorporating these epigenetic changes as biomarkers during endoscopic surveillance interval for patients with Barrett's esophagus.
巴雷特食管是一种可导致食管腺癌的癌前病变，其特征是食管正常鳞状上皮的组织学改变。在巴雷特化生向发育异常及浸润性腺癌的多阶段转变过程中会发生众多分子变化。在此过程中，表观遗传变化，尤其是DNA甲基化变化广泛存在。研究表明，在巴雷特食管中，肿瘤抑制基因、黏附分子和DNA修复基因的启动子会发生异常DNA甲基化。这些表观遗传改变可作为食管腺癌风险分层和早期检测的分子生物标志物。我们还发现，全基因组甲基化分析惊人地显示，在巴雷特化生过程中，整体低甲基化而非高甲基化才是主要变化。而巴雷特食管向浸润性腺癌的转变则以较小规模的选择性启动子高甲基化为特征。这些研究揭示了许多新的潜在治疗靶点，并说明了在巴雷特食管患者的内镜监测期间，将这些表观遗传变化作为生物标志物的实用性。
