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

我们将探索DNA的持续改变 甲基化和内分泌分化，在已建立的人肺中发现 癌症，可能标志着这些肿瘤发展的最早阶段。 的 我们的目标是开发新的生物标志物，用于早期检测和了解 肺肿瘤的发生。 使用一种固有的策略， 本SPORE提案中的项目1和项目3，我们将首先探讨这些 分离的支气管上皮细胞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 与项目4合作，我们还将研究来自 铀矿工 将在第二个系列中寻求积极的结果， 评价痰液和支气管镜检查标本中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 甲基化模式也在培养的人支气管 肺癌中基因改变的上皮细胞， 插入。 对于DNA甲基化，我们将重点关注区域超甲基化的区域 在人类肿瘤发展的早期就被发现了。 这些变化 有可能异常沉默，或标记染色质变化， 沉默，染色体上基因的表达在肺中持续改变 癌 DNA甲基转移酶（DNA-MT）表达增加 基因，也发生在结肠癌进展的早期，也将是 寻找。 对于内分泌分化，表征早期的参数 仓鼠气管上皮细胞对致癌物的反应， 与人类小细胞肺癌表型的聚类，将被研究。 这些标记物不仅可用于肺癌的早期诊断， 一般来说，也适用于SCLC。

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.