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

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.

Epigenetic Dysregulation of 5-hydroxymethylcytosine in Well-Differentiated Pancreatic Neuroendocrine Tumors

“…Epigenetic modifiers such as DNA methylation and demethylation affect global gene expression and play an important role in the pathogenesis of various cancers. 12 A substantial decrease in the amount of 5-hmC has been reported in various types of cancer, including melanoma, brain, lung, breast, liver, prostate, colon, and pancreatic ductal cancers; 11,[13][14][15][16][17][18] however, the 5-hmC levels in pancreatic neuroendocrine neoplasms remain unknown. In the present study, the loss of 5-hmC expression was seen in PanNETs with aggressive biological behavior and was significantly associated with the presence of distant metastases, high Ki-67 proliferation index, and increased tumor size, corresponding to a higher T-stage.…”

Deep5hmC: Predicting genome-wide 5-Hydroxymethylcytosine landscape via a multimodal deep learning model

“…Beyond neurodegenerative diseases, 5hmC also plays a significant role in cancer development and treatment. Genome-wide mapping of 5hmC reveals that loss of 5hmC is an epigenetic hallmark of melanoma and medulloblastoma (Lian et al, 2012; Stahl et al, 2021; Zhao et al, 2021). Additionally, 5hmC in circulating cell-free DNA serves as diagnostic biomarkers for colorectal, gastric, pancreatic cancer, acute myeloid leukemia and other common human cancer types (Gao et al, 2019; W. Li et al, 2017; Shao et al, 2022).…”

Risk Factors for Survival in Patients With Medulloblastoma: A Systematic Review and Meta-Analysis

“…Nonetheless, these parameters show limited and unreliable correlations with the prognosis of MB (10)(11)(12). Systematic reviews quantitatively assessing the potential risk factors have been published in 2010 and 2016 (13,14), but several papers have been published since (12,(15)(16)(17), providing recent assessments of traditional risk factors and new ones.…”