The isocitrate dehydrogenase 1 (IDH1) gene mutation occurs frequently in glioma. While some studies have demonstrated that IDH1 mutations are associated with prolonged survival, the mechanism remains unclear. In this study, we found that growth was significantly inhibited in glioma cells overexpressing the mutated IDH1 gene. Furthermore, these cells were characterized by decreased intracellular NADPH levels accompanied by glutathione (GSH) depletion and reactive oxygen species (ROS) generation. Moreover, the increased apoptosis and the decreased proliferation were found in the glioma cells overexpressing the mutant IDH1 gene. Accordingly, our study demonstrates that using H2O2-regulated mutant IDH1 glioma cells could obviously increase the inhibition of cell growth; nevertheless, GSH had the opposite result. Our study provides direct evidence that mutation of IDH1 profoundly inhibits the growth of glioma cells, and we speculate that this is the major factor behind its association with prolonged survival in glioma. Finally, our study indicates that depletion of GSH and generation of ROS are the primary cellular events associated with this mutation.

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In order to improve prognosis of glioma patients, better tools are required for early diagnosis and treatment. Serum cell-free DNA methylation levels of Alu, MGMT, P16, RASSF1A from 124 glioma patients and 58 healthy controls were detected by the bisulfite sequencing. The median methylation level of Alu was 46.15% (IQR, 36.57%–54.00%) and 60.85% (IQR, 57.23%–65.68%) in glioma patients and healthy controls respectively. The median methylation level of MGMT in glioma samples was 64.65% (IQR, 54.87%–74.37%) compared to 38.30% (IQR, 34.13%–45.45%) in healthy controls, and all revealed significant differences including P16. However, the median methylation level of RASSF1A was not significantly altered in glioma patients. Furthermore, the methylation levels of Alu and MGMT in serum had a good diagnostic value, and was higher than P16. Interestingly, combination of Alu and MGMT identified additional patients, which were missed by either diagnosis alone. In the Alu group, the patients with high levels were associated with an increased survival rate compared to those who with low levels, with similar results observed in the MGMT group. In the present study, we demonstrated that the methylation level of Alu and MGMT in serum had a better diagnostic value than P16. Moreover, combined analysis of Alu and MGMT showed higher sensitivity for glioma diagnosis. Therefore, both serum Alu and MGMT methylation levels may represent a novel prognostic factor for glioma patients.

Global genomic hypomethylation is a hallmark of cancer in humans. In the present study, the feasibility of measuring hypomethylation of Alu elements (Alu) in serum and its clinical utility were investigated. Tumor tissues and matched serum specimens from 65 glioma patients and serum samples from 30 healthy controls were examined for Alu hypomethylation by bisulfite sequencing. The median serum Alu methylation level was 47.30 % in patients (interquartile range (IQR), 35.40-54.25 %) and 57.90 % in the controls (IQR, 55.25-61.45 %). The median Alu methylation level in tumor samples was 40.30 % (IQR, 36.80-54.20 %), which shows the correlation of Alu hypomethylation between tumor and serum samples (r = 0.882) in the study group. The methylation level was higher in the low-grade glioma group than in the high-grade group both in tumor and serum samples. A correlation between high methylation level and longer survival time was detected in tumor and serum samples. Receiver operating characteristic curve analysis showed that the area under the curve for diagnosis was 0.861 (95 % confidence interval, 0.789-0.933), suggesting that Alu hypomethylation in serum may be of diagnostic value. Our results indicate that the detection of Alu hypomethylation in serum may be clinically useful for the diagnosis and prognosis of glioma.