Epigenetic Markers for Lung Cancer Detection

描述(申请人提供)：肺癌仍然是所有癌症中最致命的。肺癌的存活率与发病时的分期有关。由于局部肿瘤一般不会引起症状，这种疾病通常在预后较差的晚期被诊断出来。因此，肺癌的整体5年存活率仅为15%。因此，早期发现是提高生存率和预后的关键。众所周知，CpG岛的表观遗传改变与癌症有关。这些表观遗传的超甲基化可能是肺癌风险的潜在生物标志物，或者可能是早期发现。我们这项研究的目标是确定DMA启动子高甲基化作为肺癌早期检测的标志。我们之前报道了肺癌组织中21个基因的高甲基化，在全基因组限制性标志性基因组扫描(RLGS)确定这些基因上的CpG岛与邻近的非受累组织相比存在差异甲基化。与肿瘤和非受累邻近组织中的非特异性高甲基化相反，在肿瘤中发生甲基化但在邻近非受累组织中不发生甲基化的沉默基因座可能在肿瘤的发生中起关键作用。这项研究的假设是，肺癌的肿瘤进展的特征是与特定位点的启动子高甲基化相关的进行性表观遗传沉默。我们建议比较肺癌患者切除的肺肿瘤、邻近的前驱病变和正常肺组织中RLGS差异甲基化。由此产生的数据将确定在肺癌早期经常高甲基化的特定CpG岛序列。然后，我们将确定在差异高甲基化的基因座中，哪些显示了肺癌相关基因沉默。最后，使用亚硫酸氢盐修改的测序，我们将确定受影响的CpG岛内的超甲基化程度。肿瘤/前体/正常组织的甲基化图谱将在相同的患者中进行比较，因此，CpG岛差异甲基化代表癌症特异性的表观遗传学变化。这些结果可能对肺癌的早期诊断有很大的帮助。我们还可以识别与进展相关的标记物，这可能为深入了解肺癌的生物学机制提供帮助。拟议的研究将产生数据，这些数据将成为更大规模研究的基础，以验证使用已确定的甲基化位点来开发早期肺癌诊断的标记。

DESCRIPTION (provided by applicant): Lung cancer remains the most lethal of all cancers. Survival from lung cancer is related to stage at presentation. As localized tumors generally do not cause symptoms, the disease is usually diagnosed at advanced stages when the prognosis is poor. As a result, the overall 5-year lung cancer survival rate is only 15%. Therefore, early detection is essential to improve survival and prognosis. It is well known that epigenetic alterations at CpG islands are associated with cancer. These epigenetic hypermethylations can be potential biomarkers for lung cancer risk or possibly early detection. Our goal for this study is to identify DMA promoter hypermethylation as markers of early detection of lung cancer. We previously reported hypermethylation at 21 genes in lung tumor tissues after genome-wide restriction landmark genomic scanning (RLGS) determined that CpG islands at these loci were differentially methylated compared to adjacent non-involved tissue. In contrast to non-specific hypermethylation in both tumor and non-involved adjacent tissue, silenced loci that are methylated in tumor but not in adjacent noninvolved tissue may be critical to carcinogenesis. The hypothesis of this study is that neoplastic progression in lung cancer is characterized by progressive epigenetic silencing associated with promoter hypermethylation at specific loci. We propose to compare RLGS differential methylation of lung tumors, adjacent precursor lesions and normal lung tissues resected from lung cancer patients. The resulting data will identify the specific CpG island sequences frequently hypermethylated in the early stages of lung cancer. Then we will determine which among the differentially hypermethylated loci show lung cancer-associated gene silencing. Finally, using bisulfite modified sequencing, we will determine the extent of hypermethylation within the affected CpG islands. Methylation profiles in tumor/precursor/normal tissues will be compared within same patients, therefore, CpG island differential methylation represents cancer-specific epigenetic changes. These results may be of immense benefit towards the early diagnosis of lung cancer. We also can identify markers associated with progression, which may provide insight into the biological mechanism of lung cancer. The proposed study will generate data that will be the groundwork for larger studies to validate the use of the identified methylation sites to develop markers for early lung cancer diagnosis.