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


CONCLUSIONS
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.
Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Pei
P
Yang
Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Wei
W
Zhang
Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Yinyan
Y
Wang
Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, China.
Xiaoxia
X
Peng
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Baoshi
B
Chen
Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Xiaoguang
X
Qiu
Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Guilin
G
Li
Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China.
Shouwei
S
Li
Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China.
Chenxing
C
Wu
Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China.
Kun
K
Yao
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Wenbin
W
Li
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Wei
W
Yan
Center for Theoretic and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego, CA, USA.
Jie
J
Li
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Yongping
Y
You
Center for Theoretic and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego, CA, USA.
Clark C
CC
Chen
Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|China National Clinical Research Center for Neurological Diseases, Beijing, China.
Tao
T
Jiang
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D059248:Chemoradiotherapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012042:Registries; D015996:Survival Rate; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
IDH; MGMT; glioblastomas; radiation; temozolomide