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

Jiajun Cai, Chang Zeng, Wei Hua, Zengxin Qi, Yanqun Song, Xingyu Lu, Dongdong Li, Zhou Zhang, Xiaolong Cui, Xin Zhang, Zixiao Yang, Jinsen Zhang, Kai Quan, Wei Zhu, Jiabin Cai, Chuan He, Shi Yuan Cheng, Wei Zhang*, Ying Mao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 noninvasive 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 5hmC levels summarized for gene bodies, long noncoding 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 (area under the curve [AUC] = 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 noninvasive approach for effective detection of gliomas in a screening program.

Original languageEnglish (US)
Article numbervdab049
Pages (from-to)1842-1850
Number of pages9
JournalNeuro-Oncology Advances
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • 5-hydroxymethylcytosine
  • Biomarker
  • cell-free DNA
  • diagnosis
  • glioma

ASJC Scopus subject areas

  • Clinical Neurology
  • Oncology
  • Surgery

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