DNA Methylation Markers in Esophageal Adenocarcinoma

描述（由申请人提供）：近年来，人们越来越清楚，导致肿瘤发生的分子事件不仅包括基因突变，还包括表观遗传改变，如启动子CpG岛的DNA甲基化。我们已经证明，DNA甲基化变化既是肿瘤的因果因素，也是癌症的潜在生物标志物，包括食道腺癌。我们已经开发了一种敏感的、定量准确的、自动的DNA甲基化分析技术，称为MethyLight，我们已经证明DNA甲基化谱可以区分正常食管鳞状黏膜、肠化和不典型增生。这些初步结果表明，DNA甲基化标记物最终可以作为食管癌早期检测和/或监测项目风险评估的临床工具。

DESCRIPTION (provided by applicant): In recent years, it has become clear that molecular events leading to oncogenesis include not only genetic mutations, but also epigenetic alterations, such as the DNA methylation of promoter CpG islands. We have shown that DNA methylation changes are both causal contributors to neoplasia, and potential biomarkers for cancer, including adenocarcinoma of the esophagus. We have developed a sensitive, quantitatively accurate, automated DNA methylation analysis technique, called MethyLight, with which we have shown that DNA methylation profiles can discriminate between normal squamous mucosa of the esophagus, intestinal metaplasia, and dysplasia. These preliminary results suggest that DNA methylation markers could eventually be exploited as clinical tools in the early detection of esophageal adenocarcinoma and/or in risk assessment in surveillance programs. Since the 1970s, incidence rates for esophageal and gastric cardia adenocarcinomas have risen substantially, particularly among white males in the United States. Reasons for the increase of these tumor types are not well understood. We have conducted a case-control study to determine the role of smoking, alcohol use, body size characteristics, and other risk factors in the etiology of adenocarcinoma of the esophagus and gastric cardia. Here we propose to use automated MethyLight technology to generate extensive methylation profiles for tissue samples retrieved from this population-based case-control study. This will allow us to identify superior methylation markers for further development and testing as clinical tools in the early detection of esophageal adenocarcinoma, and for the differentiation of Barrett's cases that are at high risk for further progression. We will also investigate whether factors known to increase the risk of adenocarcinoma of the esophagus, increase the risk of DNA methylation in normal tissue, or in the resulting adenocarcinoma.