Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature that Correlates with Poor Outcomes in Patients with Medulloblastoma

Abstract

Background: 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. Methods: 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.Results: We observed that global 5hmC levels were decreased in medulloblastomas compared to normal cerebellums (P < 0.001). Multivariate analysis showed that low 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 was associated with protein expression of TET1 (r = -0.419, P = 0.003) and TET2 (r = -0.399, P = 0.005).Conclusions: 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.…”