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Simple Summary: Glioblastoma is the most malignant brain tumor. To date, there is no curative therapy available. Since EGFR is an interesting candidate in precision medicine, we performed an integrated molecular analysis in glioblastoma with and without EGFR amplification. We found that there are significant molecular differences in glioblastoma, depending on the EGFR amplification state. Analysis of top differences revealed DNA replication and packaging, and chromatin and gene silencing pathways. Targeting these altered pathways may open novel targets in precision medicine. 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 (EGFR) 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 EGFR amplified and non-amplified glioblastomas. We found 9849 significantly differentially methylated CpGs (DMCGs) with Δβ ≥ 0.1 and p-value < 0.05 in EGFR amplified, compared to EGFR 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 EGFR amplified glioblastomas. In summary, dissecting the methylomes of EGFR 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastomas are highly malignant brain tumors. Despite intensive research, there are no curative therapies available at the present time. Since Programmed Cell Death Ligand 1 (PD-L1) is a promising novel candidate in precision medicine, we here performed molecular analysis on glioblastomas with and without noteworthy PD-L1 expression. We found that there are severe molecular differences in glioblastomas depending on the PD-L1 state. An analysis of the top differences revealed post-transcriptional and RNA-associated pathways being altered. Targeting these altered pathways opens novel therapeutic approaches in the fight against brain cancer. Glioblastomas are the most frequent primary brain tumors in adults. They show highly malignant behavior and devastating outcomes. Since there are still no targeted therapies available, median survival remains in the range of 12 to 15 months for glioblastoma patients. Programmed Cell Death Ligand 1 (PD-L1) is a promising novel candidate in precision medicine. Here, we performed integrated epigenome-wide methylation profiling of 866,895 methylation-specific sites in 20 glioblastoma samples comparing PD-L1 high- (i.e., TPS (tumor proportion score) > 30%) and PD-L1 low-expressing glioblastomas (i.e., TPS < 10%). We found 12,597 significantly differentially methylated CpGs (DMCG) (Δβ ≥ 0.1 and p-value < 0.05) in PD-L1 high- compared with PD-L1 low-expressing glioblastomas. These DMCGs were annotated to 2546 tiling regions, 139 promoters, 107 genes, and 107 CpG islands. PD-L1 high-expressing glioblastomas showed hypomethylation in 68% of all DMCGs. Interestingly, the list of the top 100 significantly differentially methylated genes showed the enrichment of regulatory RNAs with 19 DMCGs in miRNA, snoRNAs, lincRNAs, and asRNAs. Gene Ontology analysis showed the enrichment of post-transcriptional and RNA-associated pathways in the hypermethylated gene regions. In summary, dissecting the methylomes depending on PD-L1 status revealed significant alterations in RNA regulation and novel molecular targets in glioblastomas. [ABSTRACT FROM AUTHOR]