Methylome Profiling of PD-L1-Expressing Glioblastomas Shows Enrichment of Post-Transcriptional and RNA-Associated Gene Regulation

Hutarew, Georg; Hölzl, Dorothee; Schiefer, Tanja; Langwieder, Celina K.; Alinger-Scharinger, Beate; Schlicker, H.; Schwartz, Christoph; Sotlar, Karl; Kraus, Theo

doi:10.3390/cancers14215375

Cited by 2 publications

(2 citation statements)

References 48 publications

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“…cancers (90)(91)(92). Though a lot is not known about these lincRNAs in pediatric B-ALL, they may be potential targets for follow-up.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle small RNA cargo discriminates non-cancer donors from pediatric B-lymphoblastic leukemia patients

Longjohn,

Hudson,

Peña-Castillo

et al. 2023

Front. Oncol.

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Pediatric B-acute lymphoblastic leukemia (B-ALL) is a disease of abnormally growing B lymphoblasts. Here we hypothesized that extracellular vesicles (EVs), which are nanosized particles released by all cells (including cancer cells), could be used to monitor B-ALL severity and progression by sampling plasma instead of bone marrow. EVs are especially attractive as they are present throughout the circulation regardless of the location of the originating cell. First, we used nanoparticle tracking analysis to compare EVs between non-cancer donor (NCD) and B-ALL blood plasma; we found that B-ALL plasma contains more EVs than NCD plasma. We then isolated EVs from NCD and pediatric B-ALL peripheral blood plasma using a synthetic peptide-based isolation technique (Vn96), which is clinically amenable and isolates a broad spectrum of EVs. RNA-seq analysis of small RNAs contained within the isolated EVs revealed a signature of differentially packaged and exclusively packaged RNAs that distinguish NCD from B-ALL. The plasma EVs contain a heterogenous mixture of miRNAs and fragments of long non-coding RNA (lncRNA) and messenger RNA (mRNA). Transcripts packaged in B-ALL EVs include those involved in negative cell cycle regulation, potentially suggesting that B-ALL cells may use EVs to discard gene sequences that control growth. In contrast, NCD EVs carry sequences representative of multiple organs, including brain, muscle, and epithelial cells. This signature could potentially be used to monitor B-ALL disease burden in pediatric B-ALL patients via blood draws instead of invasive bone marrow aspirates.

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“…cancers (90)(91)(92). Though a lot is not known about these lincRNAs in pediatric B-ALL, they may be potential targets for follow-up.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle small RNA cargo discriminates non-cancer donors from pediatric B-lymphoblastic leukemia patients

Longjohn,

Hudson,

Peña-Castillo

et al. 2023

Front. Oncol.

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“…We used the Genome Studio (Illumina, San Diego, CA, USA) and RnBeads [ 18 ] for methylation analysis, as previously described with identical analysis parameters [ 19 ]. Analogous to other epigenome-wide association studies (EWAS), we used nominal p -values [ 20 , 21 ].…”

Section: Methodsmentioning

confidence: 99%

Dissecting the Methylomes of EGFR-Amplified Glioblastoma Reveals Altered DNA Replication and Packaging, and Chromatin and Gene Silencing Pathways

Kraus

Langwieder

Hölzl

et al. 2023

Cancers

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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.

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Methylome Profiling of PD-L1-Expressing Glioblastomas Shows Enrichment of Post-Transcriptional and RNA-Associated Gene Regulation

Cited by 2 publications

References 48 publications

Extracellular vesicle small RNA cargo discriminates non-cancer donors from pediatric B-lymphoblastic leukemia patients

Extracellular vesicle small RNA cargo discriminates non-cancer donors from pediatric B-lymphoblastic leukemia patients

Dissecting the Methylomes of EGFR-Amplified Glioblastoma Reveals Altered DNA Replication and Packaging, and Chromatin and Gene Silencing Pathways

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