Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples
Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples
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DOI：
10.1172/jci200315475
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发表时间：
2003-03-01
影响因子：
15.9
通讯作者：
Chen, CY
中科院分区：
文献类型：
--
作者：
Wang, YC;Lu, YP;Chen, CY
我们对77名非小细胞肺癌（NSCLC）患者切除的原发性肿瘤中的hMLH 1和hMSH 2错配修复基因进行了遗传学和表观遗传学研究。检测的分子改变包括mRNA和蛋白质表达的丢失以及启动子甲基化，以及携带基因的染色体区域的等位基因不平衡。我们发现，78%和26%的患者分别在hMLH1和hMSH2基因中显示出至少一种类型的分子改变。55.8%的肿瘤中存在hMLH1基因启动子甲基化，并且与mRNA和蛋白质表达的降低显着相关（P = 0.001）。结果显示，在14例女性NSCLC患者中，hMSH2基因启动子区甲基化与mRNA表达的一致性为93%。然而，未发现hMLH1和hMSH2蛋白的表达与5个与基因紧密连锁的微卫星标记的等位基因不平衡之间的相关性。我们的研究结果表明，hMLH1是主要的改变错配修复基因参与NSCLC肿瘤的发生，启动子甲基化是hMLH1和hMSH2失调的主要机制。此外，可以在痰液样本中鉴定hMLH1基因的启动子甲基化，以作为NSCLC的潜在诊断标志物。
We performed a genetic and epigenetic study of the hMLH1 and hMSH2 mismatch repair genes in resected primary tumors from 77 non-small cell lung cancer (NSCLC) patients. The molecular alterations examined included the loss of mRNA and protein expression as well as promoter methylation, and the allelic imbalance of the chromosomal regions that harbor the genes. We found that 78% and 26% of patients showed at least one type of molecular alteration within the hMLH1 and hMSH2 genes, respectively. Promoter methylation of the hMLH1 gene was present in 55.8% of tumors, and was significantly associated with the reduction in mRNA and protein expression (P = 0.001). A 72% concordance of aberrant methylation in sputum samples with matched resected tumors was found. In addition, a 93% consistency between the promoter methylation and the mRNA expression of the hMSH2 gene was found in 14 female NSCLC patients. However, no correlation was found between the expression of hMLH1 and hMSH2 proteins and the allelic imbalance of five microsatellite markers closely linked to the genes. Our results suggest that hMLH1 is the major altered mismatch repair gene involved in NSCLC tumorigenesis, and that promoter methylation is the predominant mechanism in hMLH1 and hMSH2 deregulation. In addition, promoter methylation of the hMLH1 gene may be identified in sputum samples to serve as a potential diagnostic marker of NSCLC.