Kim Hojoong, Kwon Young Mi, Kim Jin Seuk, Han Joungho, Shim Young Mog, Park Joobae, Kim Duk-Hwan
Division of Pulmonary and Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Cancer. 2006 Sep 1;107(5):1042-9. doi: 10.1002/cncr.22087.
Despite many reports about the involvement of DNA methyltransferases (DNMTs) in human cancers, including nonsmall cell lung cancer (NSCLC), the clinicopathologic significance of DNMTs in primary NSCLC remains to be elucidated.
The relation between the mRNA levels of DNMTs (1 and 3b) and the promoter methylation of the p16, RARbeta2, H-cadherin, GSTP1, RIZ, and FHIT genes and the clinicopathologic features in 102 fresh-frozen tissues and paraffin blocks were retrospectively studied. The mRNA levels of the DNMTs were assessed via semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), and the methylation status of the CpG islands were determined by methylation-specific PCR.
The mRNA levels of DNMT1 and DNMT3b were elevated in 53% and 58% of 102 NSCLCs, respectively. Hypermethylation of p16, RARbeta2, H-cadherin, GSTP1, RIZ, and FHIT occurred in 37%, 38%, 34%, 18%, 9%, and 31% of patients, respectively. Univariate analysis showed that elevated DNMT mRNA levels were not significantly associated with the hypermethylation of 6 genes. However, the elevated mRNA levels of DNMT1 were determined to be significantly associated with the hypermethylation of the p16 promoter (odds ratio [OR] = 2.70, 95% confidence interval [95% CI], 1.02-7.15; P = .02), after controlling for age, gender, pack-years smoked, histology, and pathologic stage. The hazard of failure in cases with elevated mRNA levels of DNMT1 was 3.51 (95% CI, 1.18-12.76; P = .02) times higher than that in those without. The elevated mRNA levels of DNMT3b were not ultimately associated with patient prognosis.
Elevated mRNA expression of DNMT1 may be an independent prognostic factor in NSCLC and CpG island hypermethylation in NSCLC may be maintained by a complex interaction of several factors rather than by a simple transcriptional up-regulation of DNMT1.
尽管有许多关于DNA甲基转移酶（DNMTs）参与人类癌症（包括非小细胞肺癌（NSCLC））的报道，但DNMTs在原发性NSCLC中的临床病理意义仍有待阐明。
回顾性研究102份新鲜冷冻组织和石蜡块中DNMTs（1和3b）的mRNA水平与p16、RARβ2、H-钙黏蛋白、GSTP1、RIZ和FHIT基因启动子甲基化之间的关系以及临床病理特征。通过半定量逆转录聚合酶链反应（RT-PCR）评估DNMTs的mRNA水平，并通过甲基化特异性PCR确定CpG岛的甲基化状态。
在102例NSCLC中，DNMT1和DNMT3b的mRNA水平分别在53%和58%的病例中升高。p16、RARβ2、H-钙黏蛋白、GSTP1、RIZ和FHIT的高甲基化分别发生在37%、38%、34%、18%、9%和31%的患者中。单因素分析显示，DNMT mRNA水平升高与6个基因的高甲基化无显著相关性。然而，在控制年龄、性别、吸烟包年数、组织学和病理分期后，确定DNMT1的mRNA水平升高与p16启动子的高甲基化显著相关（优势比[OR]=2.70，95%置信区间[95%CI]，1.02 - 7.15；P = 0.02）。DNMT1的mRNA水平升高的病例失败风险比未升高的病例高3.51倍（95%CI，1.18 - 12.76；P = 0.02）。DNMT3b的mRNA水平升高最终与患者预后无关。
DNMT1的mRNA表达升高可能是NSCLC的一个独立预后因素，NSCLC中CpG岛的高甲基化可能是由多种因素的复杂相互作用维持的，而不是由DNMT1的简单转录上调维持的。
