A Meta-Analysis of the Relationship Between RARβ Gene Promoter Methylation and Non-Small Cell Lung Cancer

BackgroundHypermethylation of CpG islands in tumor suppressor gene plays an important role in carcinogenesis. Many studies have demonstrated that hypermethylation in promoter region of RARβ gene could be found with high prevalence in tumor tissue and autologous controls such as corresponding non-tumor lung tissue, sputum and plasma of the NSCLC patients. But with the small number subjects included in the individual studie, the statistical power is limited. Accordingly, we performed this meta-analysis to further asses the relationship of methylation prevalence between the cancer tissue and atuologous controls (corresponding non-tumor lung tissue, sputum and plasma).MethodsThe published articles about RARβ gene promoter hypermethyltion were identified using a systematic search strategy in PubMed, EMBASE and CNKI databases. The pooled odds ratio (OR) of RARβ promoter methylation in lung cancer tissue versus autologous controls were calculated.ResultsFinally, eleven articles, including 1347 tumor tissue samples and 1137 autologous controls were included in this meta-analysis. The pooled odds ratio of RARβ promoter methylation in cancer tissue was 3.60 (95%CI: 2.46–5.27) compared to autologous controls with random-effect model. Strong and significant correlation between tumor tissue and autologous controls of RARβ gene promoter hypermethylation prevalence across studies (Correlation coefficient 0.53) was found.ConclusionRARβ promoter methylation may play an important role in carcinogenesis of the NSCLC. With significant methylation prevalence correlation between tumor tissue and autologous of this gene, methylation detection may be a potential method for searching biomarker for NSCLC.

背景：抑癌基因（tumor suppressor gene）中CpG岛（CpG islands）的高甲基化在肿瘤发生过程中发挥重要作用。多项研究已证实，非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的肿瘤组织及对应自体对照样本（autologous controls，如配对非肿瘤肺组织、痰液及血浆）中，RARβ基因（RARβ gene）启动子区域高甲基化检出率较高。但由于单项研究纳入的研究对象数量较少，统计效力（statistical power）有限。为此，本研究开展本次荟萃分析（meta-analysis），以进一步评估癌组织与自体对照样本间的甲基化检出率关联。方法：本研究通过系统检索策略，在PubMed、EMBASE及CNKI数据库中筛选有关RARβ基因启动子高甲基化的已发表文献，计算肺癌组织相较于自体对照样本的RARβ基因启动子甲基化合并比值比（odds ratio, OR）。结果：最终，本次荟萃分析共纳入11篇文献，涉及1347份肿瘤组织样本及1137份自体对照样本。采用随机效应模型（random-effect model）分析显示，相较于自体对照样本，癌组织中RARβ基因启动子甲基化的合并比值比为3.60（95%置信区间（95% confidence interval, 95%CI）：2.46~5.27）。各研究间，RARβ基因启动子高甲基化检出率在癌组织与自体对照样本间存在显著强相关性，相关系数（correlation coefficient）为0.53。结论：RARβ基因启动子甲基化可能在非小细胞肺癌的发生发展中发挥重要作用。鉴于该基因在癌组织与自体对照样本间的甲基化检出率存在显著相关性，甲基化检测有望成为非小细胞肺癌生物标志物筛查的潜在手段。