Development of DNA Methylation Markers for Early Detection of Lung Cancer

描述（由申请人提供）：在美国，肺癌是所有种族男性和女性癌症死亡的主要原因。这种主要由吸烟引起的疾病在2005年将导致超过16万美国人死亡。2002/2003年估计有20-25%的男女和近22%的高中生吸烟。肺癌患者的生存率非常低，很大程度上是因为这种疾病很难在早期发现，而早期仍然可以通过手术治愈。先进的成像技术，如螺旋计算机断层扫描，可以对肺部进行高分辨率的检查，但在长期重度吸烟者中经常观察到不发展为肺癌的病变。可以在早期肺癌患者体液中检测到的分子标记将是成像技术的一个非常强大的补充，它将允许从可疑病变中识别真正的肺癌患者。DNA超甲基化是DNA的一种修饰，它不会改变其序列，但会改变基因表达的能力。在癌症中经常观察到异常增加的甲基化，它会导致正常情况下控制细胞生长和细胞存活的基因沉默。迄今为止，已经确定了一些显示甲基化增加的基因，但其中许多基因在肺癌中甲基化的比例不够高，不足以作为有用的标志物。利用南加州大学开发的高通量系统，Laird-Offringa实验室最近发现了一些在肺癌中高度甲基化的非常强的候选标记物。该提案旨在通过300个存档肺标本和300个匹配的对照非肿瘤肺（来自同一患者）以及100个转移到肺部的非肺癌标本，在所有主要类型的非小细胞肺癌中验证这些标记物。将检查所有主要种族（白人、黑人、西班牙裔/拉丁裔和亚洲/太平洋岛民）的肺标本。这些标志物通过分析患者体液检测肺癌的能力将通过一种新的定量技术来确定，该技术将检查300名在大学医院、莫里斯癌症中心和洛杉矶县医院接受治疗的肺癌患者的血浆、痰液和/或细支气管肺泡。开发敏感、特异的肺癌分子标志物是早期发现肺癌的关键，可大大提高肺癌患者的生存率。

DESCRIPTION (provided by applicant): In the United States, lung cancer is the leading cause of cancer death in men and women of all ethnic groups. This disease, which is mainly caused by smoking, will kill over 160,000 Americans in 2005. In 2002/2003 it was estimated that 20-25% of men and women and almost 22% of high school students smoke. Survival of lung cancer patients is very poor, largely because the disease is difficult to detect at an early stage, when it could still be cured by surgery. Advanced imaging techniques such as spiral computed tomography allow high resolution examination of the lung, but lesions that do not progress to lung cancer are very frequently observed in longtime heavy smokers. Molecular markers that could be detected in the bodily fluids of early stage lung cancer patients would be a very powerful and complementary addition to imaging techniques, that would allow the identification of true lung cancer patients from among those with suspicious lesions. DNA hypermethylation is a modification of DNA that does not change its sequence, but that alters the ability of genes to be expressed. Abnormally increased methylation is frequently observed in cancer, where it causes the silencing of genes that normally keep cell growth and cell survival in check. To date, a number of genes showing increased methylation have been identified, but many of these genes are not methylated in a high enough percentage of lung cancers to be useful as markers. Using a high-throughput system developed at USC, the Laird-Offringa laboratory has recently identified a number of very strong candidate markers that are hypermethylated in lung cancer. This proposal is aimed at validating these markers in all major types of non-small cell lung cancer using 300 archival lung specimens and 300 matched control non-tumor lung (from the same patients), as well as 100 non-lung cancers that metastasized to the lung. Lung specimens from all major ethnic groups (white, black, Hispanic/Latino and Asian/Pacific Islander) will be examined. The ability of these markers to detect lung cancer through the analysis of patient bodily fluids will be determined using a new quantitative technique to examine the plasma, sputum and/or bronchioalveloar wash of 300 lung cancer patients treated at University Hospital, Morris Cancer Center, and Los Angeles County Hospital. The development of sensitive and specific molecular markers for lung cancer is the key to early detection of this disease, and could greatly increase lung cancer patient survival.