IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry
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Pei Yang1,2,*, Wei Zhang1,2,*, Yinyan Wang1,2, Xiaoxia Peng3, Baoshi Chen2, Xiaoguang Qiu4, Guilin Li6, Shouwei Li7, Chenxing Wu7, Kun Yao8, Wenbin Li9, Wei Yan10, Jie Li11, Yongping You10, Clark C. Chen11, Tao Jiang1,2,5
1Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
3Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, China
4Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
5China National Clinical Research Center for Neurological Diseases, Beijing, China
6Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
7Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
8Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
9Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
10Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
11Center for Theoretic and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego, CA, USA
*These authors have contributed equally to this work
Tao Jiang, e-mail: [email protected]
Clark Chen, e-mail: [email protected]
Yongping You, e-mail: [email protected]
Keywords: glioblastomas, IDH, MGMT, temozolomide, radiation
Received: June 10, 2015 Accepted: September 13, 2015 Published: October 12, 2015
Background: The relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood.
Methods: We investigated the association between methMGMT and mIDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients.
Results: For 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.
Conclusion: Our 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.
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