DNA METHYLATION/NEUROENDOCRINE DIFFERENTIATION--MARKING EARLY STATE LUNG CANCER

我们将探索DNA持续变化的可能性 在已建立的人肺中发现甲基化和内分泌分化 癌症，可能标志着这些肿瘤发展的最早阶段。这个 目标是开发新的生物标志物，用于早期发现和了解 肺肿瘤发生过程中的事件。使用一种固有的策略 项目1和项目3在这个孢子提案中，我们将首先探讨这些 慢性支气管炎患者分离的支气管上皮和已建立的肿瘤的变化 每种主要组织学类型的肺癌患者。在……里面 与项目4合作，我们还将研究来自 铀矿工。积极的发现将在第二个系列中进行 支气管镜检查和痰标本检测标记物有效性的研究 有患肺癌风险的患者。在平行研究中，DNA 在培养的人支气管中也在探索甲基化模式。 肺癌中基因改变成的上皮细胞 已插入。 对于DNA甲基化，我们将重点关注区域高甲基化领域 早在人类肿瘤进展过程中就已被发现。这些变化 有可能异常沉默，或标记染色质变化， 沉默，染色体上的基因表达在肺中持续变化 癌症。DNA-甲基转移酶的表达增加 基因，这也发生在结肠癌进展的早期，也将是 被追寻。对于内分泌分化，早期表征的参数 仓鼠气管上皮对致癌物的细胞反应 聚集性与人类小细胞肺癌的表型，将被研究。 这些标记物不仅对肺癌的早期诊断有用，而且 通用的，但也是专门针对SCLC的。

We will be exploring the possibility that consistent alterations of DNA methylation and endocrine differentiation, found in established human lung cancers, may mark the earliest stages of development of these tumors. The goal is to develop new biomarkers for early detection and for understanding events in the genesis of lung neoplasms. Using a strategy inherent to Projects 1 and 3 in this SPORE proposal, we will first explore these changes in isolated bronchial epithelium and established tumors from patients with each of the major histologic types of lung cancer. In collaboration with Project 4, we will also study similar samples from uranium miners. Positive findings will be pursued in a second series of studies to evaluate marker efficacy in sputum and bronchoscopy specimens of patients at risk for developing lung cancer. In parallel studies, DNA methylation patterns are also being explored in cultured human bronchial epithelial cells into which genes altered in lung cancers have been inserted. For DNA methylation, we will focus on areas of regional hypermethylation which have been found, early, in human tumor progression. These changes have potential for abnormally silencing, or marking chromatin changes which silence, expression of genes on chromosomes consistently altered in lung cancer. Increases in expression of the DNA-methyltransferase (DNA-MT) gene, which also occur early in colon cancer progression, will also be sought. For endocrine differentiation, parameters which characterize early cellular responses of hamster tracheal epithelium to carcinogens, and which cluster with the human small cell lung cancer phenotype, will be studied. These markers may not only be useful for early diagnosis of lung cancer, in general, but also specifically for SCLC.