Differential Hypermethylation of Death-Associated Protein Kinase Promoter in Central Neurocytoma and Oligodendroglioma

Abstract

Background. Central neurocytoma and oligodendroglioma are rare tumors of the central nervous system. However, diagnosis between these two types of tumors is challenging due to their many cytological and histological similarities. Death-associated protein kinase (DAPK) is a calcium/calmodulin-regulated serine/threonine protein kinase involved in many apoptosis pathways, and repressed expression of DAPK by promoter hypermethylation has been found in a variety of human cancers. The purpose of this study was to assess DAPK protein expression and promoter hypermethylation in central neurocytoma and oligodendroglioma. Method. Central neurocytoma and oligodendroglioma samples were obtained from age- and sex-matched patients. DAPK protein expression was performed using immunohistochemical assays in formalin-fixed, paraffin-embedded sections. DAPK promoter hypermethylation was carried out using bisulfite-modified genomic DNA in methylation-specific PCR followed by separation in agarose gels. Findings. A statistically significant difference (P = 0.021) in DAPK promoter hypermethylation between central neurocytoma (76.9%) and oligodendroglioma (20%) was observed. High levels of DAPK protein expression were generally found in oligodendroglioma (90%), compared with 38.5% in central neurocytoma (P = 0.054; not statistically significant). There was an inverse correlation between DAPK protein expression and DAPK promoter hypermethylation in the cohort of 23 patients (P = 0.002). Conclusions. The results show that DAPK promoter hypermethylation and repressed expression of DAPK protein were more common in central neurocytoma than in oligodendroglioma. Thus, DAPK promoter hypermethylation could be useful for differential diagnosis between these two types of tumors, whereas DAPK protein expression might be less predictive. The role of DAPK promoter hypermethylation in the pathogenesis of central neurocytoma warrants further study.

Central neurocytoma exhibits radial glial cell signatures with FGFR3 hypomethylation and overexpression

“…Commonly observed genomic alterations previously reported in various types of CNS tumors, such as IDH1, IDH2, TP53, NF1, SMARCB1, FUBP1, and ATRX mutations , PTEN deletion, EGFR amplification, and 1p/19q deletion 45 , were also checked and found to be absent in CN. Previous studies of CN involving karyotyping and target sequencing were also unable to establish any key genomic events as drivers of CN tumorigenesis 10 , 46 – 50 . In light of these data, we posited that specific genomic alterations might not initiate CN tumorigenesis.…”

“…However, due to the rarity of these tumors, research related to CN is limited, especially in regard to comprehensive genomic studies using the most recent technology. To date, only six studies involving CN have included sequencing results (based on microarray, karyotyping, and target sequencing) 10 , 46 – 50 . In this study, to address this knowledge gap, we performed genomic profiling of CN using next-generation sequencing technologies such as WES, bulk and snRNA-seq, and methyl-seq to determine the key elements underlying CN development.…”