DNA Damage Response Markers in Barrett's Esophagus

描述(由申请人提供)： 食管腺癌(EAC)在美国的发病率正在显著增加。五年存活率仍然是令人失望的15%。迫切需要更好的方法来检测EAC高危患者并阻断疾病进展。肠化生，一种通常被称为巴雷特食道的情况，与EAC的风险增加有关。巴雷特氏异型增生的组织病理学诊断提示了进一步的风险，但病理学家之间的一致性很差。需要改进的标记物来准确地指导临床决策，并在预防EAC发展的干预研究中作为有效的替代终点。Barrett病的进展与基因组的不稳定性有关，例如反映DNA损伤发生的DNA拷贝数的变化。此外，到目前为止，在Barrett进展中已被发现的两个主要的、机械上重要的致癌事件使可由DNA损伤检查点反应诱导的细胞周期抑制物失活。在肠道肿瘤中可以检测到这种反应的激活，但在Barrett病中还没有得到很好的研究。我们提出了一个模型，在Barrett病中，疾病的进展是由DNA损伤驱动的，由DNA损伤检查点反应逆转，并在检查点失效时加速。在Barrett手术切除标本的免疫组织化学研究中，我们已经获得了支持这一模型的初步证据。我们建议将这些研究扩展到内窥镜活检和刷检样本，目的是确定进展为EAC的临床有用标记物。来自现有组织库的活检组织将被染色为细胞周期蛋白A、磷酸化组蛋白H3和？H_2AX，以评估它们与组织病理学诊断以及进展为高度异型增生和EAC的相关性。预期将收集活组织检查和内窥镜刷检。将在这些样本中检测细胞周期和检查点标记，以评估它们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.