Lung Cancer Diagnosis Using DNA Methylation Signatures

描述(由申请人提供)：CpG岛高甲基化(在基因启动子区域的CpG二核苷酸组的背景下胞嘧啶的异常甲基化)是肿瘤抑制基因在癌症发展过程中被沉默的常见机制。不同的癌症类型表现出不同的DNA高甲基化模式。因此，对肺癌样本中足够的DNA甲基化位点的分析应该会产生在许多癌症中普遍甲基化的基因座，以及在肺癌中唯一甲基化的基因座。肺癌特异性DNA高甲基化模式的确定将有助于准确诊断肺癌的组织亚型，与治疗反应和生存等临床病理数据相关联(导致建立预测标记)，最后，在未来，通过识别肺癌高危人群血清和痰中的甲基化变化，开发早期检测工具。然而，到目前为止，对肺癌的DNA甲基化研究仅限于单基因或少量基因座，这些基因的甲基化频率还不够高，不足以具有足够的诊断价值。为了将DNA甲基化分析应用于肺癌的准确诊断或早期检测，需要确定对不同组织亚型肺癌具有高度敏感性和特异性的基因或基因组合。在这里，我们建议筛选一个由100个基因组成的小组，以确定在肺癌或某些肺癌亚型中高甲基化的基因座。然后，我们将评估单个基因座和多个基因座组合作为一般肺癌标志物或肺癌亚型的标志物。最后，我们将检查甲基化数据，以确定甲基化模式与临床病理特征和总存活率的相关性。这项拟议的研究将产生的数据将成为更大规模前瞻性研究的基础，以验证已识别的甲基化标志物的使用，以研究肺癌患者和肺癌高危人群的样本(癌症标本、痰和血清)，目的是开发肺癌诊断、治疗选择、结果预测和复发检测的标志物。

DESCRIPTION (provided by applicant): CpG island hypermethylation (the abnormal methylation of cytosine in the context of groups of CpG dinucleotides in the promoter regions of genes) is a common mechanism by which tumor suppressor genes are silenced during cancer development. Different cancer types show distinct patterns of DNA hypermethylation. Thus, analysis of sufficient DNA methylation loci in lung cancer samples should yield loci that are commonly methylated in many cancers, as well as loci that are uniquely methylated in lung cancer. The determination of DNA hypermethylation patterns specific for lung cancer would allow accurate diagnosis of the histological subtype of lung cancer, correlation to clinico-pathological data such as response to treatment and survival (leading to the establishment if predictive markers), and finally, in the future, the development of early detection tools through the identification of methylation changes in the serum and sputum of subjects at risk for lung cancer. To date, however, DNA methylation studies of lung cancer have been limited to single gene loci, or small numbers of loci, which are not hypermethylated at a high enough frequency to be of sufficient diagnostic value. For DNA methylation analysis to be applicable to the accurate diagnosis or early detection of lung cancer, a gene or combination of genes with high sensitivity and specificity for the various histological subtypes of lung cancer needs to be identified. Here we propose to screen a panel of 100 genes to identify loci that are hypermethylated in lung cancer or in certain lung cancer subtypes. We will then evaluate individual loci and panels of loci as general lung cancer markers or markers for lung cancer subtypes. Lastly, we will examine the methylation data to identify correlations of methylation patterns with clinico-pathological features and overall survival. The proposed study will yield data that will form the basis for much larger prospective studies to validate the use of the identified methylation markers to study samples (cancer specimens, sputum and serum) from lung cancer patients and subjects at risk for lung cancer, with the goal to develop markers for lung cancer diagnosis, selection of therapy, prediction of outcome, and detection of recurrence.