Aberrant promoter methylation profile and association with survival in patients with non-small cell lung cancer
Aberrant promoter methylation profile and association with survival in patients with non-small cell lung cancer
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DOI：
10.1158/1078-0432.ccr-06-0894
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发表时间：
2006-12-15
影响因子：
11.5
通讯作者：
Wu, Xifeng
中科院分区：
文献类型：
--
作者：
Gu, Jian;Berman, David;Wu, Xifeng
目的：本研究的目的是探讨抑癌基因高甲基化对非小细胞肺癌 (NSCLC) 患者的预后价值。实验设计：我们使用定量甲基化特异性 PCR 检查了 155 个 NSCLC 患者肿瘤中 9 个基因的甲基化状态。我们分析了基因甲基化状态与患者总体生存率之间的关联。结果：甲基化指数（定义为甲基化基因数量与测试基因数量之间的比率）在腺癌中显着高于鳞状细胞癌（0.38 +/- 0.20）（0.30 +/- 0.22；P = 0.027），在老年患者肿瘤中显着高于年轻患者（0.37 +/- 0.20） （0.30 +/- 0.22；P = 0.040），重度吸烟者的肿瘤（0.39 +/- 0.21）高于轻度吸烟者（0.29 +/- 0.20；P = 0.042）。在 Cox 比例风险模型中，p16 甲基化与显着较差的生存率相关[风险比，1.95； 95% 置信区间 (95% CI), 1.21-3.39]。 Kaplan-Meier 生存曲线显示，p16 高甲基化患者的生存期（中位 = 21.7 个月）明显短于 p16 无高甲基化的患者（中位 = 62.5 个月；P = 0.0001，对数秩检验）。 CDH1 或 TIMP3 基因的高甲基化与显着更好的生存相关，风险比分别为 0.51 (95% Cl, 0.29-0.90) 和 0.59 (95% Cl, 0.36-0.97)。这三个基因的联合分析显示，随着不利事件数量的增加，生存率呈显着下降趋势（P = 0.0007）。结论：多个基因的高甲基化对 NSCLC 患者的生存率表现出显着的差异性影响。需要评估每个甲基化基因对生存的影响，以提供最佳的预后价值。
Purpose: The aim of this study was to investigate the prognostic value of hypermethylation of tumor suppressor genes in patients with non-small cell lung cancer (NSCLC).Experimental Design: We examined the methylation status of nine genes in 155 tumors from patients with NSCLC using quantitative methylation-specific PCR. We analyzed the associations between gene methylation status and overall patient survival.Results: The methylation index, defined as the ratio between the number of methylated genes and the number of genes tested, was significantly higher in adenocarcinomas (0.38 +/- 0.20) than in squamous cell carcinomas (0.30 +/- 0.22; P = 0.027), in tumors from older patients (0.37 +/- 0.20) than younger patients (0.30 +/- 0.22; P = 0.040), and in tumors from heavier smokers (0.39 +/- 0.21) than lighter smokers (0.29 +/- 0.20; P = 0.042). In the Cox proportional hazards model, p16 methylation was associated with significantly poorer survival [hazard ratio, 1.95; 95% confidence interval (95% CI), 1.21-3.39]. Kaplan-Meier survival curves showed that patients with hypermethylated p16 had significantly shorter survival (median = 21.7 months) than patients without p16 hypermethylation (median = 62.5 months; P = 0.0001, log-rank test). Hypermethylation of CDH1 or TIMP3 gene was associated with significantly better survival with hazard ratios of 0.51 (95% Cl, 0.29-0.90) and 0.59 (95% Cl, 0.36-0.97), respectively. Joint analysis of these three genes showed a significant trend for poorer survival as the number of unfavorable events increased (P = 0.0007).Conclusion: Hypermethylation of multiple genes exhibited significant differential effect on NSCLC patient survival. Assessment of the effect of each methylated gene on survival is needed to provide optimal prognostic value.