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

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 i...

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Autores principales: Zhao, Fu, Zhang, Zhi-Wei, Zhang, Jing, Zhang, Shun, Zhang, Heng, Zhao, Chi, Chen, Yang, Luo, Lin, Tong, Wei-Min, Li, Chunde, Niu, Yamei, Liu, Pinan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945595/
https://www.ncbi.nlm.nih.gov/pubmed/33718152
http://dx.doi.org/10.3389/fonc.2021.603686
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author Zhao, Fu
Zhang, Zhi-Wei
Zhang, Jing
Zhang, Shun
Zhang, Heng
Zhao, Chi
Chen, Yang
Luo, Lin
Tong, Wei-Min
Li, Chunde
Niu, Yamei
Liu, Pinan
author_facet Zhao, Fu
Zhang, Zhi-Wei
Zhang, Jing
Zhang, Shun
Zhang, Heng
Zhao, Chi
Chen, Yang
Luo, Lin
Tong, Wei-Min
Li, Chunde
Niu, Yamei
Liu, Pinan
author_sort Zhao, Fu
collection PubMed
description 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.
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spelling pubmed-79455952021-03-11 Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma Zhao, Fu Zhang, Zhi-Wei Zhang, Jing Zhang, Shun Zhang, Heng Zhao, Chi Chen, Yang Luo, Lin Tong, Wei-Min Li, Chunde Niu, Yamei Liu, Pinan Front Oncol Oncology 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. Frontiers Media S.A. 2021-02-24 /pmc/articles/PMC7945595/ /pubmed/33718152 http://dx.doi.org/10.3389/fonc.2021.603686 Text en Copyright © 2021 Zhao, Zhang, Zhang, Zhang, Zhang, Zhao, Chen, Luo, Tong, Li, Niu and Liu http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Zhao, Fu
Zhang, Zhi-Wei
Zhang, Jing
Zhang, Shun
Zhang, Heng
Zhao, Chi
Chen, Yang
Luo, Lin
Tong, Wei-Min
Li, Chunde
Niu, Yamei
Liu, Pinan
Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma
title Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma
title_full Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma
title_fullStr Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma
title_full_unstemmed Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma
title_short Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma
title_sort loss of 5-hydroxymethylcytosine as an epigenetic signature that correlates with poor outcomes in patients with medulloblastoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945595/
https://www.ncbi.nlm.nih.gov/pubmed/33718152
http://dx.doi.org/10.3389/fonc.2021.603686
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