Iwadate Yasuo, Suganami Akiko, Tamura Yutaka, Matsutani Tomoo, Hirono Seiichiro, Shinozaki Natsuki, Hiwasa Takaki, Takiguchi Masaki, Saeki Naokatsu
Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Department of Bioinformatics, Chiba University Graduate School of Medicine, Chiba, Japan.
Neurosurgery. 2017 Feb 1;80(2):248-256. doi: 10.1093/neuros/nyw026.
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.
基因组DNA的低甲基化可诱导癌细胞产生干细胞特性，并导致各种恶性肿瘤产生治疗抗性。
研究胶质母细胞瘤（GBM）患者中干细胞相关基因的甲基化状态与治疗结果之间的相关性。
使用HumanMethylation450 BeadChips检测全基因组DNA甲基化状态，并比较预后良好组（生存>4年）和预后不良组（生存<1年）患者之间的甲基化状态。在70例GBM和60例少突胶质细胞瘤中，对低甲基化基因翻译的蛋白质进行免疫组织化学检测，这些蛋白质包括碱性磷酸酶（ALPL）、CD133和CD44。
难治性GBM的基因组DNA比生存时间相对较长患者的GBM甲基化程度更低（P = 0.0111）。包括ALPL、CD133和CD44在内的干细胞相关基因也显著低甲基化。一项使用免疫组织化学的验证研究表明，DNA低甲基化与ALPL、CD133和CD44的高蛋白表达密切相关。生存时间短的GBM患者这些干细胞标志物表达较高。多变量分析证实，ALPL + CD133或ALPL + CD44的共表达是生存时间短的有力预测指标。无异柠檬酸脱氢酶1突变的间变性少突胶质细胞瘤与ALPL高表达及不良生存显著相关。
异常DNA低甲基化导致的干细胞特性积累与GBM的难治性相关。
