Promoter hypermethylation of the O6-methylguanine-DNA methyltransferase gene: more common in lung adenocarcinomas from never-smokers than smokers and associated with tumor progression.
Promoter hypermethylation of the O6-methylguanine-DNA methyltransferase gene: more common in lung adenocarcinomas from never-smokers than smokers and associated with tumor progression.
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发表时间：
2003-08
期刊：
影响因子：
11.2
通讯作者：
L. C. Pulling;K. K. Divine-K.;D. Klinge;F. Gilliland;Terri Kang;A. Schwartz;T. Bocklage;S. Belinsky
中科院分区：
文献类型：
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作者：
L. C. Pulling;K. K. Divine-K.;D. Klinge;F. Gilliland;Terri Kang;A. Schwartz;T. Bocklage;S. Belinsky
腺癌 (AC) 是美国最常见的肺癌类型，占吸烟者肿瘤的 40% 和从不吸烟者肿瘤的 50-80%。直接或二手香烟烟雾的暴露以及氡子体形式的辐射是吸烟者和从不吸烟者患肺 AC 的主要危险因素。本研究的目的是确定吸烟者 (n = 157)、前铀矿工 (n = 34) 和从不吸烟者 (n = 46) 的中枢或外周 AC 的大样本中 O(6)-甲基鸟嘌呤 -DNA 甲基转移酶 (MGMT) 启动子甲基化的患病率。测定 K-ras 基因密码子 12 的突变率，以评估该癌基因的激活是否与 MGMT 甲基化相关。 MGMT 甲基化的总体患病率为 51%。与吸烟者相比，从不吸烟者的肿瘤显着更多地表现出 MGMT 甲基化（分别为 66% 和 47%）。相比之下，通过铀矿开采接触氡气并不影响甲基化的发生率。 MGMT 甲基化频率显着增加，与肿瘤分期相关。在 24% 的 AC 中检测到 K-ras 突变，在从不吸烟者、吸烟者和矿工的肿瘤中分别检测到 22%、24% 和 28%。仅 11% 的 AC 中出现 K-ras 和 MGMT 基因的改变。 Kaplan-Meier 生存估计并未揭示有或没有 MGMT 甲基化的患者生存之间的任何差异。相比之下，与具有颠换突变的患者相比，具有 K-ras 基因过渡突变的患者在诊断后最初 60 个月内的生存率显着降低。这项研究表明 MGMT 启动子高甲基化是肺早期 AC 进展中的常见事件。我们已经表明，从不吸烟者中 MGMT 甲基化的发生率明显高于吸烟者，并且在从不吸烟者中检测到 K-ras 基因内的突变频率比以前报道的更高。这项研究还表明 K-ras 激活与 MGMT 甲基化无关。
Adenocarcinoma (AC) is the most common type of lung cancer diagnosed in the United States, comprising up to 40% of tumors in smokers and 50-80% of tumors in never-smokers. Exposures to cigarette smoke, direct or second-hand, and radiation in the form of radon progeny are the major risk factors for lung AC in both smokers and never-smokers. The goal of the current study was to determine the prevalence for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in a large sample of central or peripheral ACs from smokers (n = 157), former uranium miners (n = 34), and never-smokers (n = 46). The mutation rate at codon 12 of the K-ras gene was determined to assess whether activation of this oncogene was associated with MGMT methylation. The overall prevalence for MGMT methylation was 51%. Significantly more tumors from never-smokers than smokers exhibited MGMT methylation (66 versus 47%, respectively). In contrast, exposure to radon through uranium mining did not affect the prevalence for methylation. The frequency of MGMT methylation was increased significantly in association with tumor stage. K-ras mutations were detected in 24% of all ACs and 22, 24, and 28% of tumors from never-smokers, smokers, and miners, respectively. Alterations in both the K-ras and MGMT genes were seen in only 11% of ACs. Kaplan-Meier survival estimates did not reveal any difference between patient survival with or without MGMT methylation. In contrast, survival was significantly reduced over the initial 60 months after diagnosis for patients with a transition mutation in the K-ras gene compared with those with a transversion mutation. This investigation demonstrates that MGMT promoter hypermethylation is a common event in the progression of early stage AC of the lung. We have shown that the incidence of MGMT methylation was significantly higher in never-smokers than smokers and have detected a higher frequency of mutations within the K-ras gene than previously reported in never-smokers. This study also suggests that K-ras activation is independent of MGMT methylation.