Promoter hypermethylation of RASSF1A and RUNX3 genes as an independent prognostic prediction marker in surgically resected non-small cell lung cancers.
Promoter hypermethylation of RASSF1A and RUNX3 genes as an independent prognostic prediction marker in surgically resected non-small cell lung cancers.
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DOI：
10.1016/j.lungcan.2007.05.011
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发表时间：
2007-10
期刊：
影响因子：
5.3
通讯作者：
N. Yanagawa;G. Tamura;H. Oizumi;N. Kanauchi;M. Endoh;M. Sadahiro;T. Motoyama
中科院分区：
文献类型：
--
作者：
N. Yanagawa;G. Tamura;H. Oizumi;N. Kanauchi;M. Endoh;M. Sadahiro;T. Motoyama
已知启动子 CpG 岛的异常甲基化是肿瘤抑制基因和肿瘤相关基因的主要失活机制。一些已发表的研究表明，一些基因的甲基化状态与非小细胞肺癌（NSCLC）的预后之间存在关系；在非小细胞肺癌治愈性切除后，特定基因的高甲基化有望作为预后的生物标志物。为了确定手术切除后 NSCLC 患者抑癌基因与肿瘤相关基因的甲基化状态以及临床病理特征（包括生存率）之间的关系，我们通过甲基化特异性 PCR 研究了 101 例 NSCLC 病例中 10 个基因（DAPK、FHIT、H-cadherin、MGMT、p14、p16、RAR-β、RASSF1A、RUNX3 和 TIMP-3）的甲基化情况（MSP）。 NSCLC中检查的10个基因的甲基化频率为DAPK为26%，FHIT为34%，H-钙粘蛋白为26%，MGMT为14%，p14为8%，p16为27%，RAR-β为38%，RASSF1A为42%，RUNX3为25%，TIMP-3为12%。临床病理学上，单因素分析显示，RASSF1A、RUNX3或H-cadherin甲基化状态呈阳性的各个疾病阶段的患者与这些基因甲基化状态呈阴性的患者相比，生存期显着缩短（RASSF1A：P=0.023，RUNX3：P=0.035，H-cadherin：P=0.039）。此后，虽然我们的检查仅限于 I 期疾病患者，但在单变量分析中，发现 RASSF1A 或 RUNX3 甲基化状态呈阳性的患者的生存期明显短于这些基因的甲基化状态呈阴性的患者 (RASSF1A:P=0.022，RUNX3:P<0.01)。接下来，我们发现组织学差异是，具有 RUNX3 甲基化的患者在腺癌 (AC) 中的生存期较短 (P=0.045)，而具有 RASSF1A 甲基化的患者在鳞状细胞癌 (SCC) 中的生存期较短 (P=0.021)。在多变量分析中，发现RASSF1A甲基化状态阳性和RUNX3甲基化状态阳性是独立的预后因素（RASSF1A：P=0.031，RUNX3：P=0.028），TNM分期（P=0.004）和胸膜受累（P=0.037）也是如此。总之，RASSF1A 或 RUNX3 基因的高甲基化是预测 NSCLC 预后的有用生物标志物，特别是 RASSF1A 因 SCC 和 RUNX3 因 AC 所致。
Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of the tumor suppressor and tumor-related genes. Some published studies suggest a relationship to exist between the methylation status of several genes and the prognosis in non-small cell lung cancer (NSCLC); hypermethylation of the specific genes may be expected to serve as a biomarker for the prognosis, after a curative resection of NSCLC. To determine the relationship between the methylation status of the tumor suppressor and the tumor-related genes, and the clinicopathologic characteristics, including the survival rate, in patients with NSCLC after a surgical resection, we studied methylation in 10 genes (DAPK, FHIT, H-cadherin, MGMT, p14, p16, RAR-β, RASSF1A, RUNX3, and TIMP-3) in 101 NSCLC cases by methylation-specific PCR (MSP). The methylation frequencies of the 10 genes examined in NSCLC were 26% for DAPK, 34% for FHIT, 26% for H-cadherin, 14% for MGMT, 8% for p14, 27% for p16, 38% for RAR-β, 42% for RASSF1A, 25% for RUNX3, and 12% for TIMP-3. Clinicopathologically, the patients with all stages of disease who had positive RASSF1A, RUNX3, or H-cadherin methylation status were found to have a significantly shorter duration of survival, as compared with the patients with a negative methylation status for those genes (RASSF1A:P=0.023, RUNX3:P=0.035, H-cadherin:P=0.039) in univariate analysis. Thereafter, while limiting our examination to patients with stage I disease, the patients who had a positive RASSF1A or RUNX3 methylation status were found to have a significantly shorter duration of survival, in comparison to the patients with negative methyaltion status for each of those genes (RASSF1A:P=0.022, RUNX3:P<0.01) in univariate analysis. Next, the histological differences were recognized that the patients with RUNX3 methylation had a shorter duration of survival in adenocarcinomas (ACs) (P=0.045), in contrast to those with RASSF1A methylation who had a shorter duration of survival in squamous cell carcinomas (SCCs) (P=0.021). In multivariate analysis, both positive RASSF1A methylation status, and positive RUNX3 methylation status were found to be independent prognostic factors (RASSF1A:P=0.031, RUNX3:P=0.028), as was TNM stage (P=0.004) and pleural involvement (P=0.037). In conclusion, the hypermethylation of RASSF1A or RUNX3 gene is therefore a useful biomarker to predict the prognosis in NSCLC, particularly RASSF1A due to SCCs and RUNX3 due to ACs.