Methylation and transcription patterns are distinct in IDH mutant gliomas compared to other IDH mutant cancers.
Methylation and transcription patterns are distinct in IDH mutant gliomas compared to other IDH mutant cancers.
复制标题
与其他 IDH 突变癌症相比，IDH 突变神经胶质瘤的甲基化和转录模式是不同的。
DOI：
10.1038/s41598-019-45346-1
复制
发表时间：
2019
影响因子：
4.6
通讯作者：
Horbinski,Craig
中科院分区：
文献类型：
--
作者：
Unruh,Dusten;Zewde,Makda;Buss,Adam;Drumm,MichaelR;Tran,AnhN;Scholtens,DeniseM;Horbinski,Craig
异柠檬酸脱氢酶1和2（IDHmut）突变存在于多种癌症中，包括神经胶质瘤、急性髓性白血病（AML）、黑色素瘤和胆管癌。这些突变促进了高甲基化，但它只是胶质瘤的一个有利的预后标志物，原因尚不清楚。我们假设DNA甲基化模式和转录组图谱在IDHmutcancers，特别是胶质瘤中会有所不同。使用Illumina 450 K和来自癌症基因组图谱的RNA-Seq数据，我们显示在365，092个分析的CpG位点中，与野生型（IDHwt）胶质瘤相比，IDHmutglioma中有70，591个（19%）是高甲基化的，并且相对于IDHwt对应物，IDHmutAML，黑素瘤和胆管癌中只有3%，2%和4%的CpG位点是高甲基化的。转录组差异显示，促恶性基因似乎是独特的IDHmutgliomas。然而，参与分化和免疫反应的基因在所有IDHmutcancers中被抑制。此外，IDHmut在未分化的神经祖细胞中比在成熟的星形胶质细胞中引起更大程度的超甲基化。这些数据表明IDHmut诱导的基因组高甲基化的程度和靶点根据细胞环境而变化很大，这可能有助于解释为什么IDHmut仅是胶质瘤中的有利预后标志物。
Mutations inisocitrate dehydrogenases1 and 2 (IDHmut) are present in a variety of cancers, including glioma, acute myeloid leukemia (AML), melanoma, and cholangiocarcinoma. These mutations promote hypermethylation, yet it is only a favorable prognostic marker in glioma, for reasons that are unclear. We hypothesized that the patterns of DNA methylation, and transcriptome profiles, would vary among IDHmutcancers, especially gliomas. Using Illumina 450K and RNA-Seq data from The Cancer Genome Atlas, we show that of 365,092 analyzed CpG sites, 70,591 (19%) were hypermethylated in IDHmutgliomas compared to wild-type (IDHwt) gliomas, and only 3%, 2%, and 4% of CpG sites were hypermethylated in IDHmutAML, melanoma, and cholangiocarcinoma, relative to each of their IDHwtcounterparts. Transcriptome differences showed pro-malignant genes that appear to be unique to IDHmutgliomas. However, genes involved in differentiation and immune response were suppressed in all IDHmutcancers. Additionally, IDHmutcaused a greater degree of hypermethylation in undifferentiated neural progenitor cells than in mature astrocytes. These data suggest that the extent and targets of IDHmut-induced genomic hypermethylation vary greatly according to the cellular context and may help explain why IDHmutis only a favorable prognostic marker in gliomas.