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DNA Methylation subclass Receptor Tyrosine Kinase II (RTK II) is predictive for seizure development in glioblastoma patients

ABSTRACT: Background: Seizures can present at any time before or after the diagnosis of a glioma. Roughly, 25-30 % of glioblastoma (GBM) patients initially present with seizures, and an additional 30 % develop seizures during the course of the disease. Early studies failed to show an effect of general administration of anti-epileptic drugs for glioblastoma patients, since they were unable to stratify patients into high- or low- risk seizure groups. Methods: 112 patients, who underwent surgery for a GBM, were included. Genome- wide DNA methylation profiling was performed, before methylation subclasses and copy number changes inferred from methylation data were correlated with clinical characteristics. Independently, global gene expression was analyzed in GBM methylation subclasses from TCGA datasets (n=68). Results: Receptor tyrosine Kinase (RTK) II GBM showed a significantly higher incidence of seizures than RTK I and mesenchymal (MES) GBM (p<0.01). Accordingly, RNA expression datasets revealed an upregulation of genes involved in neurotransmitter synapses and vesicle transport in RTK II glioblastomas. In a multivariate analysis, temporal location (p=0.01, OR 6.35) and RTK II (p=0.03, OR 5.56) were most predictive for preoperative seizures. During postoperative follow-up, only RTK II remained significantly associated with the development of seizures (p<0.01, OR 8.23). Consequently, the need for antiepileptic medication and its increase due to treatment failure was highly associated with the RTK II methylation subclass (p<0.01). Conclusion: Our study shows a strong correlation of RTK II glioblastomas with preoperative and long-term seizures. These results underline the benefit of molecular glioblastoma profiling with important implications for postoperative seizure control.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188547 | GEO | 2021/11/13

REPOSITORIES: GEO

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Project description:This SuperSeries is composed of the SubSeries listed below. BACKGROUND: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to the subgroup of methylguanin-O6-methyltransferase promoter (MGMT) hypermethylated tumors. Further resistance markers and pathways against chemotherapy and radiotherapy are largely unknown and would help for better stratification. METHODS: The diagnostic cohorts involved clinical data and methylation profiles of the NOA-08 (n = 104, elderly glioblastoma) and the EORTC 26101 (n = 297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg center. Twenty-eight glioblastoma CpGs from 17 DNA damage response (DDR) genes that negatively correlate with expression derived from a 450 DDR gene list as well as telomerase reverse transcriptase (TERT) promoter mutations were investigated for outcome and interaction with therapy and classifier assignments. RESULTS: CpG methylation in IDH wildtype tumors had the highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) I glioblastoma subgroup. MES tumors have lower tumor purity and differ in copy number variations on chromosomes 7 and 10 from the RTK I and II subtypes. CpG hypomethylation of DDR genes (TP73, CCND3, CSNK1E, EXO1, CUL4A and PRPF19) correlated with worse patient survival in particular in MGMT unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival in primary glioblastoma. Primary glioma cells show methylation pattern that resemble RTK I and II glioma and differ from long term established cell lines. Knock-down of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide treatment in vitro. CONCLUSION: Methylation of DDR genes and TERT promoter mutations are associated with tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in high-grade glioma.

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DNA Methylation subclass Receptor Tyrosine Kinase II (RTK II) is predictive for seizure development in glioblastoma patients

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