DNA methylation and protein expression of Wnt pathway markers in progressive glioblastoma

Tompa, Márton; Kajtár, Béla; Gálik, Bence; Gyenesei, Attila; Kálmán, Bernadette

doi:10.1016/j.prp.2021.153429

Cited by 2 publications

(5 citation statements)

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“…In our previous studies, we used the RRBS technology to identify DMPs, and performed simultaneous epigenomic and protein expression analyses for the two most affected (Wnt and catecholamine) pathways in progressive GBM samples [ 5 , 6 , 7 ]. In this study, we presented the third group of the most differentially methylated pathways, the immune pathways in longitudinal GBM samples, to highlight a previously not reported DMP, the IL-7/IL-7 receptor pathway, with significant practical relevance.…”

Section: Discussionmentioning

confidence: 99%

“…None of the patients were alive at the time of the initiation of the original epigenomic analyses in 2018–2019 [ 5 ]; the histological diagnoses of the obtained tumor specimens were based on the 2016 WHO guideline [ 12 ]. As additional immunohistochemical studies were subsequently also performed and reported on the same tissue specimens [ 5 , 6 , 7 ], no sufficient tissue remained for complementary testing of those molecular alterations (i.e., H3F3A, HIST1H3B, HIST1H3C, TERT, EGFR-amplification) recommended in the 2021 WHO revision [ 13 ]. As Table S1 shows, however, all tumors were late-onset GBMs, and thus mutations in histone proteins would be very unlikely.…”

Section: Methodsmentioning

confidence: 99%

“…Methylomes of five epilepsy surgery specimens (CG) obtained from the European Nucleotide Archive [ 14 ] ( , Primary Accession: PRJNA391429; EGAS00001002538 accessed on 17 June 2022) were used as controls in the DNA CpG methylation analyses in comparisons with GBM prim and GBM rec [ 5 , 6 , 7 ].…”

Section: Methodsmentioning

confidence: 99%

“…We observed that analyzing CpG sites only within the (approx. 2000 bp) gene promoters in our relatively small cohorts could not provide statistically meaningful outcomes for defining differential methylation [ 6 , 7 ]. The methylation levels were expressed as percentages where the numerators were calculated from the numbers of methylated sites (with the degree of methylation also computed into the figures), and the denominators were the numbers of all CpG sites within the investigated region, and multiplied by 100.…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study, relying on the Restricted Resolution Bisulfite Sequencing (RRBS) technology, we detected several differentially methylated pathways (DMP) in primary and recurrent FFPE GBM specimens [ 5 ]. Subsequently, we further investigated the most outstanding DMPs, the Wnt and catecholamine pathways, by comparing the promoter and gene methylation profiles with protein expression levels of their elements in the same specimens [ 6 , 7 ]. In the present study, we investigated in more depth the third-most outstanding DMP, the immune pathways that have not been previously scrutinized [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

et al. 2022

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Background: Immune evasion in glioblastoma (GBM) shields cancer cells from cytotoxic immune response. Methods: We investigated CpG methylation in promoters, genes, and pathways in 22 pairs of formalin-fixed paraffin-embedded sequential (FFPE) GBM using restricted resolution bisulfite sequencing (RRBS) and bioinformatic analyses. Results: Gene ontology revealed hypermethylation in elements of the innate and adaptive immune system when recurrent GBM samples (GBMrec) were compared to control (CG) and primary GBM samples (GBMprim). Higher methylation levels of the IL-7 signaling pathway and response to IL-7 were found in GBMrec suggesting a progressive blockade of the IL-7 driven T cell response in sequential GBM. Analyses of the Cancer Genome Atlas array-based data confirmed hypermethylation of the IL-7 pathway in recurrent compared with primary GBM. We also quantified DNA CpG methylation in promoter and gene regions of the IL-7 ligand and IL-7 α-receptor subunit in individual samples of a large RRBS-based sequential cohort of GBM in a Viennese database and found significantly higher methylation levels in the IL-7 receptor α-subunit in GBMrec compared with GBMprim. Conclusions: This study revealed the progressive suppression of the IL-7 receptor-mediated pathway as a means of immune evasion by GBM and thereby highlighted it as a new treatment target.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

et al. 2022

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On the Boundary of Exploratory Genomics and Translation in Sequential Glioblastoma

Tompa,

Galik,

Urban

et al. 2024

IJMS

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OMICS methods brought significant advancements to the understanding of tumor cell biology, which transformed the treatment and prognosis of several cancers. Clinical practice and outcomes, however, changed significantly less in the case of glioblastoma (GBM). In this study, we aimed to assess the utility of whole exome (WES) sequencing in the clinical setting. Ten pairs of formalin-fixed, paraffin-embedded (FFPE) GBM specimens were obtained at onset (GBM-P) and at recurrence (GBM-R). Histopathological and molecular features of all samples supported the diagnosis of GBM based on WHO CNS5. WES data were filtered, applying a strict and custom-made pipeline, and occurrence of oncogenic and likely oncogenic variants in GBM-P, GBM-R or both were identified by using the VarSeq program version 2.5.0 (Golden Helix, Inc.). Characteristics and recurrence of the variants were analyzed in our own cohort and were also compared to those available in the COSMIC database. The lists of oncogenic and likely oncogenic variants corresponded to those identified in other studies. The average number of these variants were 4 and 5 out of all detected 24 and 34 variants in GBM-P and GBM-R samples, respectively. On average, one shared oncogenic/likely oncogenic variant was found in the pairs. We assessed the identified variants’ therapeutic significance, also taking into consideration the guidelines by the Association for Molecular Pathology (AMP). Our data support that a thorough WES analysis is suitable for identifying oncogenic and likely oncogenic variants in an individual clinical sample or a small cohort of FFPE glioma specimens, which concur with those of comprehensive research studies. Such analyses also allow us to monitor molecular dynamics of sequential GBM. In addition, careful evaluation of data according to the AMP guideline reveal that though therapeutic applicability of the variants is generally limited in the clinic, such information may be valuable in selected cases, and can support innovative preclinical and clinical trials.

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DNA methylation and protein expression of Wnt pathway markers in progressive glioblastoma

Cited by 2 publications

References 42 publications

Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

On the Boundary of Exploratory Genomics and Translation in Sequential Glioblastoma

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