Vallböhmer Daniel, Brabender Jan, Yang Dongyun, Schneider Paul M, Metzger Ralf, Danenberg Kathleen D, Hölscher Arnulf H, Danenberg Peter V
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
Clin Lung Cancer. 2006 Jul;8(1):39-44. doi: 10.3816/CLC.2006.n.031.
A significant association between aberrant methylation in regulatory regions of tumor suppressor genes and clinical outcome in various different cancer types has been described. The molecular events for this epigenetic alteration still remain unknown. Evidence suggests that overexpression of DNA methyltransferases (DNMTs) is one potential mechanism for hypermethylation.
Therefore, we investigated the influence of gene expression levels of the 3 DNMT isoforms (DNMT1, DNMT3a, and DNMT3b) and the hypermethylation of adenomatous polyposis coli (APC), the death-associated protein kinase (DAPK), glutathione S-transferase Pi (GSTPI), and the DNA repair gene O6-methylguanine DNA transferase (MGMT) in the pathogenesis and prognosis of patients with non-small cell lung cancer and determined their association to each other. Using a quantitative real-time reverse-transcriptase polymerase chain reaction, we measured messenger RNA expression of DNMT1, DNMT3a, and DNMT3b and DNA hypermethylation of APC, DAPK, GSTPI, and MGMT in 91 matching tumor and nonmalignant lung tissue samples from patients with curatively resected non-small-cell lung cancer.
In tumor tissue, the expression of all 3 DNMT isoforms was significantly higher compared with matched normal-appearing tissue (P < 0.001). Hypermethylation in tumor tissue was found in 95% for APC, in 92% for DAPK, in 18% for GSTPI, and in 38% for MGMT.
No correlation was found between the DNMT messenger RNA expression and DNA hypermethylation status in tumor tissues. Multivariate analysis revealed DNA hypermethylation status and TNM stage as independent prognostic factors.
肿瘤抑制基因调控区域的异常甲基化与多种不同癌症类型的临床结局之间存在显著关联。这种表观遗传改变的分子机制仍不清楚。有证据表明，DNA甲基转移酶（DNMTs）的过表达是高甲基化的一种潜在机制。
因此，我们研究了3种DNMT亚型（DNMT1、DNMT3a和DNMT3b）的基因表达水平以及腺瘤性结肠息肉病（APC）、死亡相关蛋白激酶（DAPK）、谷胱甘肽S-转移酶Pi（GSTPI）和DNA修复基因O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）的高甲基化在非小细胞肺癌患者发病机制和预后中的影响，并确定它们之间的相互关系。我们使用定量实时逆转录聚合酶链反应，测量了91例接受根治性切除的非小细胞肺癌患者的配对肿瘤和非恶性肺组织样本中DNMT1、DNMT3a和DNMT3b的信使RNA表达以及APC、DAPK、GSTPI和MGMT的DNA高甲基化情况。
与配对的外观正常组织相比，肿瘤组织中所有3种DNMT亚型的表达均显著升高（P < 0.001）。肿瘤组织中APC的高甲基化率为95%，DAPK为92%，GSTPI为18%，MGMT为38%。
未发现肿瘤组织中DNMT信使RNA表达与DNA高甲基化状态之间存在相关性。多变量分析显示DNA高甲基化状态和TNM分期是独立的预后因素。
