• Pei Yang, Wei Zhang, Yinyan Wang, Xiaoxia Peng, Baoshi Chen, Xiaoguang Qiu, Guilin Li, Shouwei Li, Chenxing Wu, Kun Yao, Wenbin Li, Wei Yan, Jie Li, Yongping You, Clark C Chen, and Tao Jiang.
• Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
• Oncotarget. 2015 Dec 1; 6 (38): 40896-906.

BackgroundThe relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood.MethodsWe investigated the association between methMGMT and mIDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients.ResultsFor glioblastoma patients who underwent Temozolomide and Radiation Therapy, OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS: 35.8 mo, median PFS: 27.5 mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo, mPFS: 9.7 mo). For patients with wtIDH glioblastomas, TMZ+RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo, p < 0.001; PFS: 9.9 mo v 6.5 mo, p < 0.001). While TMZ+RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ+RT or RT group. These results suggest that mIDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3-10 fold increase in TMZ resistance after long-term passage.ConclusionsOur study demonstrates IDH mutation and MGMT promoter methylation status independently associate with favorable outcome in TMZ+RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response.

53 keywords...

hide…