DNA Damage Response Markers in Barrett's Esophagus

描述（由申请人提供）： 在美国，食管腺癌（EAC）的发病率正在显著增加。五年生存率仍然是令人失望的15%。迫切需要更好的方法来检测EAC高风险患者并阻止疾病进展。肠上皮化生，一种通常被称为巴雷特食管的疾病，与EAC的风险增加有关。组织病理学诊断为Barrett's发育异常提示进一步的风险，但病理学家之间的一致性较差。需要改进的标志物来准确地指导临床决策，并在干预研究中作为有效的替代终点，以防止EAC的发展。Barrett's的进展与基因组不稳定性有关，例如DNA拷贝数的变化，这反映了DNA损伤的发生。此外，迄今为止已经确定的Barrett进展中的两个主要的、在机制上重要的致癌事件是DNA损伤检查点反应可以诱导的细胞周期抑制剂。这种反应的激活可以在肠肿瘤中检测到，但在巴雷特氏病中还没有得到很好的研究。我们提出了一个模型，其中巴雷特的疾病进展是由DNA损伤驱动的，由DNA损伤检查点响应取消，并在检查点失败时加速。我们已经获得了初步的证据来支持这个模型在巴雷特的手术切除标本的免疫组化研究。我们建议将这些研究扩展到内镜活检和刷检样本，目的是确定临床上有用的EAC进展标志物。从现有的组织库活检将染色细胞周期蛋白A，磷酸化组蛋白H3，和？H2AX，以评估其与组织病理学诊断以及与进展为高度异型增生和EAC的相关性。将前瞻性收集活检和内镜刷检。将在这些样本中测定细胞周期和检查点标志物，以评估其预测疾病进展的能力。

DESCRIPTION (provided by applicant): The incidence of esophageal adenocarcinoma (EAC) in the United States is increasing markedly. Five-year survival remains a disappointing 15%. Better methods are urgently needed to detect patients at high risk of EAC and to interrupt disease progression. Intestinal metaplasia, a condition commonly referred to as Barrett's esophagus, is associated with increased risk of EAC. A histopathological diagnosis of dysplasia in Barrett's indicates further risk but shows poor agreement among pathologists. Improved markers are needed to accurately guide clinical decisions and to serve as effective surrogate endpoints in studies of interventions to prevent development of EAC. Progression in Barrett's is associated with genomic instability, such as changes in changes in DNA copy number, that reflect the occurrence of DNA damage. Furthermore, the two principal, mechanistically important oncogenic events in Barrett's progression that have been identified to date inactivate cell cycle inhibitors that can be induced by the DNA damage checkpoint response. Activation of this response can be detected in intestinal neoplasia but has not been well studied in Barrett's. We propose a model in which disease progression in Barrett's is driven by DNA damage, countermanded by the DNA damage checkpoint response, and accelerated when the checkpoint fails. We have obtained preliminary evidence to support this model in immunohistochemical studies of Barrett's surgical resection specimens. We propose to extend these studies to endoscopic biopsy and brushing samples, with the goal of identifying clinically useful markers for progression to EAC. Biopsies from existing tissue banks will be stained for cyclin A, phosphorylated histone H3, and ?H2AX, to assess their correlation with histopathological diagnosis and with progression to high-grade dysplasia and EAC. Biopsies and endoscopic brushings will be prospectively collected. Cell cycle and checkpoint markers will be assayed in these samples to assess their ability to predict disease progression.