MGMT gene silencing and benefit from temozolomide in glioblastoma

被引:5358
作者
Hegi, ME
Diserens, A
Gorlia, T
Hamou, M
de Tribolet, N
Weller, M
Kros, JM
Hainfellner, JA
Mason, W
Mariani, L
Bromberg, JEC
Hau, P
Mirimanoff, RO
Cairncross, JG
Janzer, RC
Stupp, R
机构
[1] Univ Lausanne Hosp, Dept Neurosurg, Lab Tumor Biol & Genet, Lausanne, Switzerland
[2] Univ Lausanne Hosp, Dept Radiotherapy, Lausanne, Switzerland
[3] Univ Lausanne Hosp, Dept Neuropathol, Lausanne, Switzerland
[4] Univ Lausanne Hosp, Multidisciplinary Oncol Ctr, Lausanne, Switzerland
[5] Univ Hosp Geneva, Dept Neurosurg, Geneva, Switzerland
[6] Swiss Inst Expt Canc Res, Natl Ctr Competence Res Mol Oncol, CH-1066 Epalinges, Switzerland
[7] Univ Bern, Inselspital, Dept Neurosurg, CH-3010 Bern, Switzerland
[8] European Org Res Treatment Canc, Ctr Data, Brussels, Belgium
[9] Univ Tubingen, Dept Neurol, D-7400 Tubingen, Germany
[10] Univ Regensburg, Dept Neurol, D-8400 Regensburg, Germany
[11] Univ Rotterdam Hosp, Div Neuropathol, Rotterdam, Netherlands
[12] Univ Med Ctr, Utrecht, Netherlands
[13] Med Univ Vienna, Inst Neurol, Vienna, Austria
[14] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada
[15] Univ Calgary, Calgary, AB, Canada
关键词
D O I
10.1056/NEJMoa043331
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND: Epigenetic silencing of the MGMT (O(sup 6)-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.
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收藏
页码:997 / 1003
页数:7
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