Kraus Theo F J, Langwieder Celina K, Hölzl Dorothee, Hutarew Georg, Schlicker Hans U, Alinger-Scharinger Beate, Schwartz Christoph, Sotlar Karl
Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Müllner Hauptstr. 48, A-5020 Salzburg, Austria.
Department of Neurosurgery, University Hospital Salzburg, Paracelsus Medical University, Ignaz-Harrer-Str. 79, A-5020 Salzburg, Austria.
Cancers (Basel). 2023 Jul 7;15(13):3525. doi: 10.3390/cancers15133525.
Glioblastoma IDH wildtype is the most frequent brain tumor in adults. It shows a highly malignant behavior and devastating outcomes. To date, there is still no targeted therapy available; thus, patients' median survival is limited to 12-15 months. Epithelial growth factor receptor () is an interesting targetable candidate in advanced precision medicine for brain tumor patients. In this study, we performed integrated epigenome-wide DNA-methylation profiling of 866,895 methylation specific sites in 50 glioblastoma IDH wildtype samples, comparing amplified and non-amplified glioblastomas. We found 9849 significantly differentially methylated CpGs (DMCGs) with Δβ ≥ 0.1 and -value < 0.05 in amplified, compared to non-amplified glioblastomas. Of these DMCGs, 2380 were annotated with tiling (2090), promoter (117), gene (69) and CpG islands (104); 7460 are located at other loci. Interestingly, the list of differentially methylated genes allocated eleven functionally relevant RNAs: five miRNAs (miR1180, miR1255B1, miR126, miR128-2, miR3125), two long non-coding RNAs (LINC00474, LINC01091), and four antisense RNAs (EPN2-AS1, MNX1-AS2, NKX2-2-AS1, WWTR1-AS1). Gene ontology (GO) analysis showed enrichment of "DNA replication-dependent nucleosome assembly", "chromatin silencing at rDNA", "regulation of gene silencing by miRNA", "DNA packaging", "posttranscriptional gene silencing", "gene silencing by RNA", "negative regulation of gene expression, epigenetic", "regulation of gene silencing", "protein-DNA complex subunit organization", and "DNA replication-independent nucleosome organization" pathways being hypomethylated in amplified glioblastomas. In summary, dissecting the methylomes of amplified and non-amplified glioblastomas revealed altered DNA replication, DNA packaging, chromatin silencing and gene silencing pathways, opening potential novel targets for future precision medicine.
胶质母细胞瘤异柠檬酸脱氢酶（IDH）野生型是成人中最常见的脑肿瘤。它表现出高度恶性的行为和毁灭性的后果。迄今为止，仍然没有可用的靶向治疗方法；因此，患者的中位生存期限制在12至15个月。表皮生长因子受体（）是脑肿瘤患者先进精准医学中一个有趣的可靶向候选对象。在本研究中，我们对50个胶质母细胞瘤IDH野生型样本中的866,895个甲基化特异性位点进行了全表观基因组DNA甲基化分析，比较了扩增和未扩增的胶质母细胞瘤。我们发现，与未扩增的胶质母细胞瘤相比，在扩增的胶质母细胞瘤中有9849个甲基化差异显著的CpG（DMCG），Δβ≥0.1且P值<0.05。在这些DMCG中，2380个被注释为覆盖（2090个）、启动子（117个）、基因（69个）和CpG岛（104个）；7460个位于其他位点。有趣的是，差异甲基化基因列表中包含11种功能相关的RNA：5种miRNA（miR1180、miR1255B1、miR126、miR128 - 2、miR3125）、2种长链非编码RNA（LINC00474、LINC01091）和4种反义RNA（EPN2 - AS1、MNX1 - AS2、NKX2 - 2 - AS1、WWTR1 - AS1）。基因本体（GO）分析显示，在扩增的胶质母细胞瘤中，“DNA复制依赖性核小体组装”、“rDNA处的染色质沉默”、“miRNA对基因沉默的调控”、“DNA包装”、“转录后基因沉默”、“RNA介导的基因沉默”、“基因表达的负调控，表观遗传”、“基因沉默的调控”、“蛋白质 - DNA复合亚基组织”和“DNA复制非依赖性核小体组织”等途径发生低甲基化。总之，剖析扩增和未扩增的胶质母细胞瘤的甲基化组揭示了DNA复制、DNA包装、染色质沉默和基因沉默途径的改变，为未来的精准医学开辟了潜在的新靶点。
Zotero 插件
