Identifying CpG sites with different differential methylation frequencies in colorectal cancer tissues based on individualized differential methylation analysis.
Identifying CpG sites with different differential methylation frequencies in colorectal cancer tissues based on individualized differential methylation analysis.
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基于个体差异甲基化分析识别结直肠癌组织中不同差异甲基化频率的CpG位点
DOI：
10.18632/oncotarget.17647
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发表时间：
2017-07-18
期刊：
影响因子：
--
通讯作者：
Guo Z
中科院分区：
文献类型：
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作者：
Yan H;He J;Guan Q;Cai H;Zhang L;Zheng W;Qi L;Zhang S;Liu H;Li H;Zhao W;Yang S;Guo Z
大肠癌的高度异质性是其临床诊断和治疗面临的一大挑战，因此，除了亚型特异性生物标志物外，寻找大肠癌的共同生物标志物具有重要意义。在此，我们利用不同实验室的DNA甲基化数据，首次揭示了在结直肠正常组织中CpG位点的相对甲基化水平排序（RMOs）是高度稳定的，但在结直肠癌组织中被广泛破坏。这一发现为使用RankComp算法通过将个体样本内的RMO与正常组织中预定的稳定RMO进行比较来鉴定每个个体CRC样本中的差异甲基化（DM）CpG位点提供了基础。对于75个CRC样本，RankComp平均每个样本检测到4，062个DM CpG位点，并且就每个癌症样本检测到的DM CpG位点的高甲基化或低甲基化状态与该癌症样本与其配对的相邻正常样本之间观察到的差异一致而言，平均精确度达到91.34%。最后，我们应用RankComp来识别来自癌症基因组图谱的268个CRC样本中的每一个的DM CpG位点，并在268个CRC样本中的95%以上中分别发现了26个和143个基因，其启动子区域包括高甲基化和低甲基化的CpG位点。个体化途径分析确定了在超过90%的CRC组织中显著富集DM基因的6个途径。这些通用的DNA甲基化标志物可能成为结直肠癌重要的诊断标志物和治疗靶点。
A big challenge to clinical diagnosis and therapy of colorectal cancer (CRC) is its extreme heterogeneity, and thus it would be of special importance if we could find common biomarkers besides subtype-specific biomarkers for CRC. Here, with DNA methylation data produced by different laboratories, we firstly revealed that the relative methylation-level orderings (RMOs) of CpG sites within colorectal normal tissues are highly stable but widely disrupted in the CRC tissues. This finding provides the basis for using the RankComp algorithm to identify differentially methylated (DM) CpG sites in every individual CRC sample through comparing the RMOs within the individual sample with the stable RMOs predetermined in normal tissues. For 75 CRC samples, RankComp detected averagely 4,062 DM CpG sites per sample and reached an average precision of 91.34% in terms that the hypermethylation or hypomethylation states of the DM CpG sites detected for each cancer sample were consistent with the observed differences between this cancer sample and its paired adjacent normal sample. Finally, we applied RankComp to identify DM CpG sites for each of the 268 CRC samples from The Cancer Genome Atlas and found 26 and 143 genes whose promoter regions included CpG sites that were hypermethylated and hypomethylated, respectively, in more than 95% of the 268 CRC samples. Individualized pathway analysis identified six pathways that were significantly enriched with DM genes in more than 90% of the CRC tissues. These universal DNA methylation biomarkers could be important diagnostic makers and therapy targets for CRC.