Oncotarget

Research Papers:

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

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

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Oncotarget. 2015; 6:40896-40906. https://doi.org/10.18632/oncotarget.5683

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Abstract

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

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.


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