Identification of key methylation differentially expressed genes in posterior fossa ependymoma based on epigenomic and transcriptome analysis

Abstract

Background Posterior fossa ependymoma (EPN-PF) can be classified into Group A posterior fossa ependymoma (EPN-PFA) and Group B posterior fossa ependymoma (EPN-PFB) according to DNA CpG island methylation profile status and gene expression. EPN-PFA usually occurs in children younger than 5 years and has a poor prognosis. Methods Using epigenome and transcriptome microarray data, a multi-component weighted gene co-expression network analysis (WGCNA) was used to systematically identify the hub genes of EPN-PF. We downloaded two microarray datasets (GSE66354 and GSE114523) from the Gene Expression Omnibus (GEO) database. The Limma R package was used to identify differentially expressed genes (DEGs), and ChAMP R was used to analyze the differential methylation genes (DMGs) between EPN-PFA and EPN-PFB. GO and KEGG enrichment analyses were performed using the Metascape database. Results GO analysis showed that enriched genes were significantly enriched in the extracellular matrix organization, adaptive immune response, membrane raft, focal adhesion, NF-kappa B pathway, and axon guidance, as suggested by KEGG analysis. Through WGCNA, we found that MEblue had a significant correlation with EPN-PF (R = 0.69, P = 1 × 10–08) and selected the 180 hub genes in the blue module. By comparing the DEGs, DMGs, and hub genes in the co-expression network, we identified five hypermethylated, lower expressed genes in EPN-PFA (ATP4B, CCDC151, DMKN, SCN4B, and TUBA4B), and three of them were confirmed by IHC. Conclusion ssGSEA and GSVA analysis indicated that these five hub genes could lead to poor prognosis by inducing hypoxia, PI3K-Akt-mTOR, and TNFα-NFKB pathways. Further study of these dysmethylated hub genes in EPN-PF and the pathways they participate in may provides new ideas for EPN-PF treatment.

The 2021 World Health Organization Classification of Tumors of the Central Nervous System: What Neuroradiologists Need to Know

“…PF-EPNs can now be divided molecularly into 2 subgroups: PF-EPN A and PF-EPN-B. 34 ependymomas occur mainly in infants, exhibit loss of H3K27me3 expression on immunohistochemistry, exhibit EZHIP overexpression, and have significantly worse outcome than PF-EPN-B tumors. PF-EPN-B tumors are more common in older children and adults.…”

Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies

“…Pre-clinical studies on mouse ependymoma cell-lines reported that inhibition of the mTOR-pathway can induce autophagy in EPN and showed an increased survival in mice transplanted with such cell-lines when treated with sirolimus [22]. Some data also suggest an upregulation of the mTOR-pathway within EPN of the posterior fossa, with a subset of cases showing immunohistochemical staining for phosphorylated S6 [23,24]. Clinical data on the use of sirolimus in EPN is scarce and consists of one case-report and three phase I trials not specific to EPN, reporting on a total of five recurrent EPNs, showing success in some cases [24][25][26][27].…”

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

“…However, among 33 mTOR activating mutations identified in 2014 by Grabiner et al [ 231 ], those that were functionally tested in vitro conferred varying degrees of pathway activation, and, most importantly, a few displayed some substrate preference towards the eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and ribosomal protein S6 kinase (S6K1), or towards AKT1, implying that such mutations had distinct effects on mTORC1 or mTORC2. Specifically, 4EBP1 activation by mTOR1 is a major contributor to accelerated cell proliferation or increased cell survival; the so-called eIF4E-sensitive mRNAs code for various cell cycle and apoptosis regulators, including cyclins D1 and D3, CDK2, MYC, PIM1, Bcl-2, Bcl-xL and VEGF, among others [ 232 , 233 , 234 ].…”