• Yasuo Iwadate, Akiko Suganami, Yutaka Tamura, Tomoo Matsutani, Seiichiro Hirono, Natsuki Shinozaki, Takaki Hiwasa, Masaki Takiguchi, and Naokatsu Saeki.
• Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
• Neurosurgery. 2017 Feb 1; 80 (2): 248-256.

BackgroundHypomethylation of genomic DNA induces stem-cell properties in cancer cells and contributes to the treatment resistance of various malignancies.ObjectiveTo examine the correlation between the methylation status of stem-cell-related genes and the treatment outcomes in patients with glioblastoma (GBM).MethodsThe genome-wide DNA methylation status was determined using HumanMethylation450 BeadChips, and the methylation status was compared between a group of patients with good prognosis (survival > 4 yr) and a group with poor prognosis (survival < 1 yr). Immunohistochemistry for proteins translated from hypomethylated genes, including alkaline phosphatase (ALPL), CD133, and CD44, was performed in 70 GBMs and 60 oligodendroglial tumors.ResultsThe genomic DNA in refractory GBM was more hypomethylated than in GBM from patients with relatively long survival (P = .0111). Stem-cell-related genes including ALPL, CD133, and CD44 were also significantly hypomethylated. A validation study using immunohistochemistry showed that DNA hypomethylation was strongly correlated with high protein expression of ALPL, CD133, and CD44. GBM patients with short survival showed high expression of these stem-cell markers. Multivariate analysis confirmed that co-expression of ALPL + CD133 or ALPL + CD44 was a strong predictor of short survival. Anaplastic oligodendroglial tumors without isocitrate dehydrogenase 1 mutation were significantly correlated with high ALPL expression and poor survival.ConclusionAccumulation of stem-cell properties due to aberrant DNA hypomethylation is associated with the refractory nature of GBM.Copyright © 2017 by the Congress of Neurological Surgeons

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