Genome-wide CpG island methylation analyses in non-small cell lung cancer patients
Genome-wide CpG island methylation analyses in non-small cell lung cancer patients
复制标题
DOI：
10.1093/carcin/bgs363
复制
发表时间：
2013-03-01
期刊：
影响因子：
4.7
通讯作者：
Zoechbauer-Mueller, Sabine
中科院分区：
文献类型：
--
作者：
Heller, Gerwin;Babinsky, Valerie N.;Zoechbauer-Mueller, Sabine
DNA甲基化是表观遗传基因调控复合体的一部分，与癌症的发病机制有关。我们通过结合甲基化DNA免疫沉淀和微阵列分析，对101例IIII期非小细胞肺癌（NSCLC）患者的肿瘤和相应的非恶性肺组织样本中的甲基化CpG岛进行了全基因组搜索。总体而言，我们确定了2414个基因组位置之间的肿瘤和非恶性肺组织样本差异甲基化。其中97%被发现是肿瘤特异性甲基化的。这些基因组位置的注释导致了477个肿瘤特异性甲基化基因的鉴定，其中许多参与基因转录和细胞粘附的调节。通过基因特异性方法证实肿瘤特异性甲基化。在大多数肿瘤中，某些基因的甲基化与免疫组织化学测定的蛋白表达丧失相关。用表观遗传学活性药物治疗NSCLC细胞导致许多肿瘤特异性甲基化基因的表达上调，这表明这些基因中约有三分之一受甲基化的转录调控。此外，甲基化结果与患者的某些临床病理特征的比较表明，HOXA 2和HOXA 10的甲基化可能与鳞状细胞癌（SCC）患者的预后相关。总之，我们在NSCLC患者中发现了大量肿瘤特异性甲基化基因。其中许多基因的表达受甲基化调控。此外，HOXA 2和HOXA 10甲基化可作为SCC患者的预后参数。总的来说，我们的研究结果强调了甲基化对NSCLC发病机制的影响。
DNA methylation is part of the epigenetic gene regulation complex, which is relevant for the pathogenesis of cancer. We performed a genome-wide search for methylated CpG islands in tumors and corresponding non-malignant lung tissue samples of 101 stages IIII non-small cell lung cancer (NSCLC) patients by combining methylated DNA immunoprecipitation and microarray analysis. Overall, we identified 2414 genomic positions differentially methylated between tumor and non-malignant lung tissue samples. Ninety-seven percent of them were found to be tumor-specifically methylated. Annotation of these genomic positions resulted in the identification of 477 tumor-specifically methylated genes of which many are involved in regulation of gene transcription and cell adhesion. Tumor-specific methylation was confirmed by a gene-specific approach. In the majority of tumors, methylation of certain genes was associated with loss of their protein expression determined by immunohistochemistry. Treatment of NSCLC cells with epigenetically active drugs resulted in upregulated expression of many tumor-specifically methylated genes analyzed by gene expression microarrays suggesting that about one-third of these genes are transcriptionally regulated by methylation. Moreover, comparison of methylation results with certain clinicopathological characteristics of the patients suggests that methylation of HOXA2 and HOXA10 may be of prognostic relevance in squamous cell carcinoma (SCC) patients. In conclusion, we identified a large number of tumor-specifically methylated genes in NSCLC patients. Expression of many of them is regulated by methylation. Moreover, HOXA2 and HOXA10 methylation may serve as prognostic parameters in SCC patients. Overall, our findings emphasize the impact of methylation on the pathogenesis of NSCLCs.