DNA methylation biomarkers for lung cancer
DNA methylation biomarkers for lung cancer
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DOI：
10.1007/s13277-011-0282-2
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发表时间：
2012-04-01
期刊：
影响因子：
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通讯作者：
Pfeifer, Gerd P.
中科院分区：
文献类型：
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作者：
Rauch, Tibor A.;Wang, Zunde;Pfeifer, Gerd P.
DNA甲基化模式的改变是包括肺癌在内的人类癌症的一个重要特征。特别是，CpG岛的高甲基化是恶性进展的标志。甲基化的CpG岛是癌症早期检测的有希望的诊断标记。然而，肺癌中DNA高甲基化的全部范围和序列背景仍不清楚。我们使用甲基化CpG岛回收试验和高分辨率微阵列分析在肺鳞癌(SCC)和腺癌中发现了高甲基化的CpG岛。每个肿瘤都含有数百个高甲基化的CpG岛。在最初的微阵列筛查中，在5个被测试的SCC肿瘤中有5个(=100%)有36个CpG岛甲基化，在至少75%的腺癌中有52个CpG岛甲基化(n=8)。采用基于亚硫酸钠的方法，在85%到100%的鳞癌和11个CpG岛(与乍得、DLX4、GRIK2、KCNG3、NR2E1、OSR1、OTX1、OTX2、PROX1、RUNX1和VAX1基因相关)中，12个CpG岛(与BARHL2、EVX2、IRX2、Meis1、Msx1、NR2E1、OC2、OSR1、OTX1、OTX2、PROX1、RUNX1和VAX1基因)甲基化。从肺腺癌中甲基化的基因列表中，我们发现了FAT4基因，并发现该基因在39%的肿瘤中甲基化。FAT4是与果蝇肿瘤抑制因子Fat最接近的哺乳动物同源物，Fat是河马生长控制途径的重要组成部分。许多新发现的甲基化CpG岛有望成为肺癌早期检测的生物标记物。
Changes in DNA methylation patterns are an important characteristic of human cancer including lung cancer. In particular, hypermethylation of CpG islands is a signature of malignant progression. Methylated CpG islands are promising diagnostic markers for the early detection of cancer. However, the full extent and sequence context of DNA hypermethylation in lung cancer has remained unknown. We have used the methylated CpG island recovery assay and high-resolution microarray analysis to find hypermethylated CpG islands in squamous cell carcinomas (SCC) and adenocarcinomas of the lung. Each tumor contained several hundred hypermethylated CpG islands. In an initial microarray screen, 36 CpG islands were methylated in five of five (=100%) of the SCC tumors tested and 52 CpG islands were methylated in at least 75% of the adenocarcinomas tested (n = 8). Using sodium-bisulfite-based approaches, 12 CpG islands (associated with the BARHL2, EVX2, IRX2, MEIS1, MSX1, NR2E1, OC2, OSR1, OTX1, PAX6, TFAP2A, and ZNF577 genes) were confirmed to be methylated in 85% to 100% of the squamous cell carcinomas and 11 CpG islands (associated with the CHAD, DLX4, GRIK2, KCNG3, NR2E1, OSR1, OTX1, OTX2, PROX1, RUNX1, and VAX1 genes) were methylated in > 80% of the adenocarcinomas. From the list of genes that were methylated in lung adenocarcinomas, we identified the gene FAT4 and found that this gene was methylated in 39% of the tumors. FAT4 is the closest mammalian homologue of the Drosophila tumor suppressor Fat which is an important component of the Hippo growth control pathway. Many of these newly discovered methylated CpG islands hold promise for becoming biomarkers for the early detection of lung cancer.