Epigenetic Markers for Lung Cancer Detection

描述（由申请人提供）：肺癌仍然是所有癌症中最致命的。肺癌的生存率与临床分期有关。由于局部肿瘤通常不会引起症状，因此该疾病通常在预后不良的晚期被诊断出来。因此，肺癌的总体5年生存率仅为15%。因此，早期发现对改善生存和预后至关重要。众所周知，CpG岛的表观遗传改变与癌症相关。这些表观遗传高甲基化可能是肺癌风险或早期检测的潜在生物标志物。本研究的目的是鉴定DNA启动子高甲基化作为肺癌早期检测的标志物。我们先前报道了在全基因组限制性标记基因组扫描（RLGS）确定这些位点的CpG岛与相邻的非受累组织相比差异甲基化后，肺肿瘤组织中21个基因的高甲基化。与肿瘤和非受累邻近组织中的非特异性超甲基化相反，在肿瘤中甲基化但在邻近非受累组织中不甲基化的沉默位点可能对癌发生至关重要。本研究的假设是，肺癌的肿瘤进展的特点是进行性表观遗传沉默与启动子在特定基因座的高甲基化。我们建议比较肺癌患者切除的肺肿瘤、邻近的前病变和正常肺组织中RLGS的差异甲基化。由此产生的数据将确定特定的CpG岛序列经常在肺癌的早期阶段高甲基化。然后，我们将确定哪些差异高甲基化位点显示肺癌相关基因沉默。最后，使用亚硫酸氢盐修饰的测序，我们将确定受影响的CpG岛内的超甲基化程度。将在相同患者中比较肿瘤/前体/正常组织中的甲基化谱，因此，CpG岛差异甲基化代表癌症特异性表观遗传变化。这些结果可能对肺癌的早期诊断有巨大的益处。我们还可以识别与进展相关的标志物，这可能有助于深入了解肺癌的生物学机制。这项拟议的研究将产生数据，这些数据将为更大规模的研究奠定基础，以验证使用已鉴定的甲基化位点来开发早期肺癌诊断的标志物。

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.