The Pluripotent Stem-Cell Marker Alkaline Phosphatase is Highly Expressed in Refractory Glioblastoma with DNA Hypomethylation.
Hypomethylation of genomic DNA induces stem-cell properties in cancer cells and contributes to the treatment resistance of various malignancies.



To examine the correlation between the methylation status of stem-cell-related genes and the treatment outcomes in patients with glioblastoma (GBM).



The 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.



The 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.



Accumulation of stem-cell properties due to aberrant DNA hypomethylation is associated with the refractory nature of GBM.
Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Yasuo
Y
Iwadate
Department of Bioinformatics, Chiba University Graduate School of Medicine, Chiba, Japan.
Akiko
A
Suganami
Department of Bioinformatics, Chiba University Graduate School of Medicine, Chiba, Japan.
Yutaka
Y
Tamura
Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Tomoo
T
Matsutani
Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Seiichiro
S
Hirono
Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Natsuki
N
Shinozaki
Department of Biochemistry and Genetics, Chiba University Graduate School of Medicine, Chiba, Japan.
Takaki
T
Hiwasa
Department of Biochemistry and Genetics, Chiba University Graduate School of Medicine, Chiba, Japan.
Masaki
M
Takiguchi
Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Naokatsu
N
Saeki
D000469:Alkaline Phosphatase / Q000032:analysis / Q000378:metabolism*; D001932:Brain Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D019175:DNA Methylation / Q000235:genetics*; D005909:Glioblastoma / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry
D000469:Alkaline Phosphatase
Stem cell; Epigenetics; Alkaline phosphatase; ALPL; Antibody microarray; Methylation; GBM; Glioma