Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma.

Fu Zhao,Chi Zhao,Heng Zhang,Wei-Min Tong,Yang Chen,Zhi-Wei Zhang,Chunde Li,Pinan Liu,Shun Zhang,Lin Luo,Yamei Niu,Jing Zhang

doi:10.3389/fonc.2021.603686

Abstract

Medulloblastoma, as the most common malignant brain tumor in children, exhibits highly dysregulated DNA methylation. The novel epigenetic marker—5-hydroxymethylcytosine (5hmC) plays essential role in gene regulation during brain development and in brain tumors. However, the biological and clinical implications of 5hmC in medulloblastoma are still unclear. Here, we detected global 5hmC levels in two independent medulloblastoma patient cohorts (discovery cohort: n = 81; validation cohort: n = 171) using ultra-high performance liquid chromatography-tandem mass spectrometry analysis. Immunohistochemistry was used to identify the cell proliferation and expression of Ten-eleven translocation 1 and 2 (TET1/2). The prognostic impacts of covariates on progression-free survival (PFS) and overall survival (OS) were evaluated using multivariate Cox hazards regression models. We observed that global 5hmC levels were decreased in medulloblastomas compared to normal cerebellums (P < 0.001). Multivariate analysis showed that low global 5hmC levels correlated with poor PFS and OS rates (discovery cohort: PFS: P = 0.003, OS: P = 0.002; validation cohort: PFS: P = 0.0002, OS: P = 0.001). Immunohistochemistry showed an inverse correlation between 5hmC score and Ki-67 index (r = -0.747, P < 0.0001). Moreover, 5hmC score in MB samples was associated with nuclear expression of TET1 (r = -0.419, P = 0.003) and TET2 (r = -0.399, P = 0.005) proteins. Our study demonstrates that loss of 5hmC is an epigenetic biomarker in medulloblastomas. Our results indicate that 5hmC could be a candidate prognostic indicator for improving survival prediction of risk stratification in patients with medulloblastoma.

Highlights

Medulloblastoma (MB) is a malignant embryonal tumor of the cerebellum that represents over 20% of all pediatric central nervous system (CNS) neoplasm [1]
In mRNA-expression levels, we found that the levels of Teneleven translocation 1 and 2 (TET1/2) and IDH1/2 were higher in MBs (n = 1350) than in normal cerebellums (n = 291; all P < 0.001; Figure 6A)
Identifying reliable biomarkers is crucial for tailoring individual treatment strategies of patients with MB

Summary

Introduction

Medulloblastoma (MB) is a malignant embryonal tumor of the cerebellum that represents over 20% of all pediatric central nervous system (CNS) neoplasm [1]. Conventional treatments have significantly improved outcomes in recent years, survivors are frequently left with devastating neurocognitive impairment and other sequelae following such therapy [2, 3]. The purpose for developing treatment strategies in MB is to increase the survival rates for high-risk patients, and to improve the quality of life of survivors by reducing the toxicity of treatment. Recent advances have shown that MBs can be classified into at least four subgroups with distinct underlying biological and clinical features [8,9,10,11]. Identifying molecular subgroups has strong potential for improving clinical management and provides a basis for investigating the biological consequences of subgroup-specific therapeutic applications [12,13,14,15].

Methods

Results

Conclusion