DNA Methylation Markers in Esophageal Adenocarcinoma

描述(申请人提供)：近年来，导致肿瘤发生的分子事件已经变得明显，不仅包括基因突变，还包括表观遗传变化，例如启动子CpG岛的DNA甲基化。我们已经证明，DNA甲基化的变化既是肿瘤形成的原因，也是包括食管腺癌在内的癌症的潜在生物标志物。我们已经开发了一种灵敏的、定量准确的自动化DNA甲基化分析技术，称为甲基化，利用该技术，DNA甲基化图谱可以区分正常的食道鳞状黏膜、肠化生和异型增生。这些初步结果表明，DNA甲基化标志物最终可能被用作食管腺癌的早期检测和/或监测项目中的风险评估的临床工具。 自20世纪70年代以来，食道腺癌和贲门腺癌的发病率大幅上升，特别是在美国的白人男性中。这些肿瘤类型增加的原因尚不清楚。我们进行了一项病例对照研究，以确定吸烟、饮酒、体型特征和其他危险因素在食管腺癌和贲门腺癌病因中的作用。 在这里，我们建议使用自动化的甲基光技术，为从这项基于人群的病例对照研究中检索到的组织样本生成广泛的甲基化特征。这将使我们能够识别出更好的甲基化标志物，以便进一步开发和测试，作为食管腺癌早期检测的临床工具，并用于鉴别有进一步进展的高风险的巴雷特氏病例。我们还将调查已知的增加食管腺癌风险的因素，是否会增加正常组织或由此导致的腺癌中DNA甲基化的风险。

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.