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An integrative analysis of genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA detects non-invasive diagnostic markers for gliomas

ABSTRACT: Background. Gliomas, especially the high-grade glioblastomas (GBM), are highly aggressive tumors in the central nervous system (CNS) with dismal clinical outcomes. Effective biomarkers, which are not currently available, may improve clinical outcomes through early detection. We sought to develop a non-invasive diagnostic approach for gliomas based on 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA). Methods. We obtained genome-wide 5hmC profiles using the 5hmC-Seal technique in cfDNA samples from 111 prospectively enrolled patients with gliomas and 111 age-, gender-matched healthy individuals, which were split into a training set and a validation set. Integrated models comprised of 5hmC levels summarized for gene bodies, long non-coding RNAs (lncRNAs), cis-regulatory elements, and repetitive elements were developed using the elastic net regularization under a case-control design. Results. The integrated 5hmC-based models differentiated healthy individuals from gliomas (AUC [area under the curve] = 84%; 95% confidence interval [CI], 74-93%), GBM patients (AUC = 84%; 95% CI, 74-94%), WHO II-III glioma patients (AUC = 86%; 95% CI, 76-96%), regardless of IDH1 (encoding isocitrate dehydrogenase) mutation status or other glioma-related pathological features such as TERT, TP53 in the validation set. Furthermore, the 5hmC biomarkers in cfDNA showed the potential as an independent indicator from IDH1 mutation status and worked in synergy with IDH1 mutation to distinguish GBM from WHO II-III gliomas. Exploration of the 5hmC biomarkers for gliomas revealed relevance to glioma biology. Conclusions. The 5hmC-Seal in cfDNA offers the promise as a non-invasive approach for effective detection of gliomas in a screening program.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132118 | GEO | 2021/05/30

REPOSITORIES: GEO

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Project description:Background: Glioblastoma (GBM) is the most aggressive and currently incurable brain tumor with a median survival of one year in adult patients. Elucidating novel transcriptomic and epigenetic contributors to the molecular heterogeneity underlying its aggressiveness may lead to improved clinical outcomes. Methods: To identify GBM-associated 5-hydroxymethylcytosine (5hmC) and transcriptomic features as well as their cross-talks, genome-wide 5hmC and transcriptomic profiles of tissue samples from 61 patients with GBM and 9 normal controls were obtained for differential and co-regulation/co-modification analyses. Prognostic models on overall survival (OS) based on transcriptomic features and the 5hmC modifications summarized over genic regions (promoters, gene bodies) and brain-derived histone marks were developed using machine learning algorithms. Results: Despite global reduction, the majority of differential 5hmC features showed higher modification levels in GBM tumors as compared to normal controls. In addition, the bi-directional correlations between 5hmC modifications over promoter regions or gene bodies and gene expression were greatly disturbed in GBM tumors regardless of IDH1 mutation status. Phenotype-associated co-regulated 5hmC-5hmC modules and 5hmC-mRNA modules not only are enriched with different molecular pathways that are indicative of the pathogenesis of GBM, but also are of prognostic significance comparable to IDH1 mutation status. Lastly, the best-performing 5hmC model can predict patient survival at a much higher accuracy (c-index = 74%) when compared to conventional prognostic factor IDH1 (c-index = 57%), capturing the molecular characteristics of tumors that are independent of IDH1 mutation status and gene expression-based molecular subtypes. Conclusions: The 5hmC-based prognostic model offers a robust tool to predict survival in GBM patients, outperforming existing prognostic factors such as IDH1 mutations. The crosstalk between 5hmC and gene expression revealed another layer of complexity underlying the molecular heterogeneity in GBM, offering opportunities for identifying novel therapeutic targets.

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An integrative analysis of genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA detects non-invasive diagnostic markers for gliomas

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