Promoter hypermethylation of the p16 and Wif-1 genes as an independent prognostic marker in stage IA non-small cell lung cancers
Promoter hypermethylation of the p16 and Wif-1 genes as an independent prognostic marker in stage IA non-small cell lung cancers
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DOI：
10.3892/ijo_00000437
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发表时间：
2009-11-01
影响因子：
5.2
通讯作者：
Yoshino, Ichiro
中科院分区：
文献类型：
--
作者：
Yoshino, Mitsuru;Suzuki, Makoto;Yoshino, Ichiro
启动子CpG岛的高甲基化是肿瘤抑制基因失活的主要机制，其中一些被认为与非小细胞肺癌（NSCLC）患者的预后有关。因此，特异基因的高甲基化有望作为非小细胞肺癌的预后生物标志物。本研究采用甲基化特异性PCR分析了44例IA期NSCLC患者中14个基因的甲基化状态。在PTGER2（70%的病例）、DRM/Gremlin（66%）、sFRP-2（57%）、IL-12R β 2（48%）、primo（41%）、APC（39%）、CXCL12（39%）、HPP1（30%）、SPARC（30%）、sFRP-5（30%）、p16（25%）、RUNX3（20%）、sFRP-1（20%）和wi -1（16%）中检测到高甲基化。p16、sFRP-5、wi -1或CXCL12甲基化患者的无复发生存期明显短于未甲基化基因患者（p16， P=0.011; sFRP-5， P=0.030; wi -1， P=0.036; CXCL12， P=0.026）。此外，HPP1、p16或wi -1甲基化的患者总生存期显著缩短（HPP1， P=0.031; p16， P=0.026; wi -1， P=0.008）。多因素分析显示，p16甲基化影响无复发生存期和wi -1甲基化影响总生存期是最强的独立预后因素（p16， P=0.036; wi -1， P=0.035）。综上所述，p16和wi -1基因的高甲基化有可能作为预测IA期NSCLC预后的生物标志物。
Hypermethylation of promoter CpG islands is a major inactivation mechanism of tumor suppressor genes, some of which are thought to be related to the prognosis of patients with non-small cell lung cancer (NSCLC). Therefore, hypermethylation of the specific genes may be expected to serve as a prognostic biomarker for NSCLC. In this study, the methylation status of 14 genes was analyzed in 44 stage IA NSCLC cases using methylation-specific PCR. Hypermethylation was detected in PTGER2 (70% of cases), DRM/Gremlin (66%), sFRP-2 (57%), IL-12R beta 2 (48%), Reprimo (41%), APC (39%), CXCL12 (39%), HPP1 (30%), SPARC (30%), sFRP-5 (30%), p16 (25%), RUNX3 (20%), sFRP-1 (20%) and Wif-1 (16%). Patients with p16, sFRP-5, Wif-1 or CXCL12 methylation had a significantly shorter duration of relapse-free survival than their counterparts with an unmethylated gene (p16, P=0.011; sFRP-5, P=0.030, Wif-1, P=0.036; CXCL12, P=0.026). Also, those with methylated HPP1, p16 or Wif-1 had a significantly shorter duration of overall survival (HPP1, P=0.031; p16, P=0.026; Wif-1, P=0.008). Multivariate analysis revealed that p16 methylation in relapse-free survival and Wif-1 methylation in overall survival were the strongest independent prognostic factors (p16, P=0.036; Wif-1, P=0.035). In conclusion, the hypermethylation of the p16 and Wif-1 genes has potential as biomarkers that may be used to predict the prognosis of stage IA NSCLC.