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CpG二核苷酸组的背景下胞嘧啶的异常甲基化）是肿瘤发展过程中肿瘤抑制基因沉默的常见机制。不同类型的癌症表现出不同的DNA超甲基化模式。因此，对肺癌样本中足够的DNA甲基化位点进行分析，应该会得到在许多癌症中普遍甲基化的位点，以及在肺癌中独特甲基化的位点。确定肺癌特有的DNA超甲基化模式将有助于准确诊断肺癌的组织学亚型，以及与临床病理数据（如对治疗的反应和生存）的相关性（导致建立预测标记物），最后，在未来，通过鉴定肺癌风险受试者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，肺癌的DNA甲基化研究仅限于单个基因位点或少数位点，这些位点的高甲基化频率不够高，不足以具有足够的诊断价值。DNA甲基化分析要应用于肺癌的准确诊断或早期发现，需要鉴定出对肺癌各种组织学亚型具有高敏感性和特异性的基因或基因组合。在这里，我们建议筛选一组100个基因，以确定肺癌或某些肺癌亚型中高度甲基化的位点。然后，我们将评估单个基因座和基因座组作为一般肺癌标志物或肺癌亚型标志物。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生存率的相关性。拟议的研究将产生数据，为更大规模的前瞻性研究奠定基础，以验证已确定的甲基化标记物在肺癌患者和肺癌高危人群样本（癌症标本、痰液和血清）中的应用，目的是开发肺癌诊断、治疗选择、预后预测和复发检测的标记物。

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.