Promoter hypermethylation of resected bronchial margins: A field defect of changes?
Promoter hypermethylation of resected bronchial margins: A field defect of changes?
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DOI：
10.1158/1078-0432.ccr-03-0763
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发表时间：
2004-08-01
影响因子：
11.5
通讯作者：
Brock, MV
中科院分区：
文献类型：
--
作者：
Guo, MZ;House, MG;Brock, MV
目的：非小细胞肺癌切除后组织学阳性的支气管壁与局部复发导致的患者生存期缩短有关。我们假设，在没有恶性组织学证据的患者中，可以检测到支气管边缘DNA启动子的高甲基化变化，这些变化反映了原发肿瘤的表观遗传学事件。实验设计：实验设计：来自20名接受肺叶切除或更大范围切除的非小细胞肺癌患者的支气管缘、原发肿瘤、支气管肺泡液和配对的非恶性肺。疾病特异性复发是主要终点。用甲基化特异性聚合酶链式反应检测p16、MGMT、DAPK、SOCS1、RASSF1A、COX2和RARbeta基因的甲基化状态。在85%的患者中，观察到一个基因与肿瘤或支气管边缘相同的表观遗传学变化的一致性。只有一名患者在支气管边缘发生了甲基化，该基因在相应的肿瘤中没有甲基化。中位复发时间为37个月(5-71个月)。局部复发2例，转移5例。肿瘤、切缘或支气管肺泡液中DNA甲基化与局部复发或远处转移均无显著相关性。结论：非小细胞肺癌切除后支气管壁边缘多基因甲基化改变频繁。这些高甲基化异常也存在于原发肿瘤中，因此可能代表癌前病变的一个领域缺陷，发生在癌变的早期。
Purpose: Histologically positive bronchial margins after resection for non-small cell lung cancer are associated with shortened patient survival due to local recurrence. We hypothesized that DNA promoter hypermethylation changes at bronchial margins could be detected in patients with no histological evidence of malignancy and that they would reflect epigenetic events in the primary tumor.Experimental Design: Bronchial margins, primary tumor, bronchoalveolar fluid, and paired nonmalignant lung were obtained from 20 non-small cell lung cancer patients who under-went a lobectomy or greater resection. Disease-specific recurrence was the primary end point. The methylation status of p16, MGMT, DAPK, SOCS1, RASSF1A, COX2, and RARbeta was examined using methylation-specific polymerase chain reaction.Results: All malignancies had methylation in at least one locus. Concordance of one gene with an identical epigenetic change in the tumor or bronchial margin was observed in 85% of patients. Only one patient had methylation at the bronchial margin for a gene that was not methylated in the corresponding tumor. Median time to recurrence was 37 months (range, 5-71 months). There were two local recurrences and five metastases. There were no significant correlations between DNA methylation in tumor, margins, or bronchoalveolar fluid specimens and either regional recurrence or distant metastases.Conclusions: Histologically negative bronchial margins of resected non-small cell lung cancer exhibit frequent hypermethylation changes in multiple genes. These hypermethylation abnormalities are also present in the primary tumor and thus may represent a field defect of preneoplastic changes that occurs early in carcinogenesis.