IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry

// Pei Yang 1, 2, * , Wei Zhang 1, 2, * , Yinyan Wang 1, 2 , Xiaoxia Peng 3 , Baoshi Chen 2 , Xiaoguang Qiu 4 , Guilin Li 6 , Shouwei Li 7 , Chenxing Wu 7 , Kun Yao 8 , Wenbin Li 9 , Wei Yan 10 , Jie Li 11 , Yongping You 10 , Clark C. Chen 11 , Tao Jiang 1, 2, 5 1 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 3 Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, China 4 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 5 China National Clinical Research Center for Neurological Diseases, Beijing, China 6 Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 7 Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 8 Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 9 Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 10 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China 11 Center for Theoretic and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego, CA, USA * These authors have contributed equally to this work Correspondence to: Tao Jiang, e-mail: taojiang1964@163.com Clark Chen, e-mail: clarkchen@ucsd.edu Yongping You, e-mail: yypl9@njmu.edu.cn Keywords: glioblastomas, IDH, MGMT, temozolomide, radiation Received: June 10, 2015      Accepted: September 13, 2015      Published: October 12, 2015 ABSTRACT 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.