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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >DNA methylation analyses of urothelial carcinoma reveal distinct epigenetic subtypes and an association between gene copy number and methylation status
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DNA methylation analyses of urothelial carcinoma reveal distinct epigenetic subtypes and an association between gene copy number and methylation status

机译：尿路上皮癌的DNA甲基化分析揭示了不同的表观遗传亚型，并且基因拷贝数与甲基化状态之间存在关联

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We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC.
机译：我们评估了149例尿路上皮癌中27,000 CpG的DNA甲基化和拷贝数状态，并将发现结果与基因表达和突变数据相结合。甲基化与1,332个CpGs的基因表达有关，其中26％与表达呈正相关，即高甲基化和高基因表达水平。这些正相关的CpGs是特定转录因子结合位点的一部分，例如MYC和CREBP1的位点，或者位于基因体中。此外，我们发现了具有拷贝数增加，低表达和高甲基化水平的基因，揭示了甲基化与拷贝数水平之间的关联。对于发育基因，例如HOX基因和肿瘤抑制基因，通常观察到这种现象。相反，我们还鉴定了具有拷贝数增加，高表达和低甲基化水平的基因。例如，对于某些角蛋白基因观察到了这一点。肿瘤病例可根据其DNA甲基化特征分为四个亚型，称为表型。一种表型受浸润免疫细胞的存在的影响，两种表型主要由非肌肉侵袭性肿瘤组成，其余表型由肌肉侵袭性肿瘤组成。阻止胚胎干细胞分化的多梳复合蛋白EZH2在肌肉侵袭性表型的mRNA和蛋白水平上均表达增加，并且多梳靶基因和HOX基因甲基化。我们的数据强调了HOX基因沉默和EZH2表达是促进UC中未分化和侵袭性状态的机制。

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