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Neuro Oncol. 2014 Sep;16(9):1263-73. doi: 10.1093/neuonc/nou005. Epub 2014 Feb 6.

The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone.

Author information

1
Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.M., C.J.F.v.N.); Neurosurgical Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands (F.E.B., D.V., W.P.V.); Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy (S.La., C.Z., A.B., F.E.B.); Department of Pathology, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands (J.W.M.J., S.H.E.B.-S., P.W.); Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands (P.W.); Department of Neurogenetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (T.J.M.H.); Department of Neuropathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (D.T., A.A.v.T.); Neurosurgical Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands (W.P.V.); Department of Neurosurgery, St. Elisabeth Hospital Tilburg, The Netherlands (S.Le.); Department of Neurosurgery, Erasmus Medical Center, Rotterdam, The Netherlands (S.Le.); FIRC Institute of Molecular Oncology, Milan, Italy (A.B.)Present affiliation: Department of Clinical Genetics, Academic Medical Center and University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (F.E.B.); Department of Pathology, Radboud University Medical Center Nijmegen, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands (A.A.v.T.); Department of Neurology, Radboud University Medical Centre Nijmegen, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands (S.H.E.B.-S.); Department of Pathology, Stichting PAMM, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands (J.W.M.J.).

Abstract

BACKGROUND:

Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered cancer genes of which only O(6)-methylguanine-methyltransferase (MGMT) methylation is used thus far as a predictive marker in a clinical setting. We investigated the prognostic significance of genetic and epigenetic alterations in glioblastoma patients.

METHODS:

We screened 98 human glioblastoma samples for genetic and epigenetic alterations in 10 genes and chromosomal loci by PCR and multiplex ligation-dependent probe amplification (MLPA). We tested the association between these genetic and epigenetic alterations and glioblastoma patient survival. Subsequently, we developed a 2-gene survival predictor.

RESULTS:

Multivariate analyses revealed that mutations in isocitrate dehydrogenase 1 (IDH1), promoter methylation of MGMT, irradiation dosage, and Karnofsky Performance Status (KFS) were independent prognostic factors. A 2-gene predictor for glioblastoma survival was generated. Based on the genetic and epigenetic status of IDH1 and MGMT, glioblastoma patients were stratified into 3 clinically different genotypes: glioblastoma patients with IDH1mt/MGMTmet had the longest survival, followed by patients with IDH1mt/MGMTunmet or IDH1wt/MGMTmet, and patients with IDH1wt/MGMTunmet had the shortest survival. This 2-gene predictor was an independent prognostic factor and performed significantly better in predicting survival than either IDH1 mutations or MGMT methylation alone. The predictor was validated in 3 external datasets.

DISCUSSION:

The combination of IDH1 mutations and MGMT methylation outperforms either IDH1 mutations or MGMT methylation alone in predicting survival of glioblastoma patients. This information will help to increase our understanding of glioblastoma biology, and it may be helpful for baseline comparisons in future clinical trials.

KEYWORDS:

IDH1; MGMT; genetic and epigenetic; glioblastoma; survival prediction

PMID:
24510240
PMCID:
PMC4136888
DOI:
10.1093/neuonc/nou005
[Indexed for MEDLINE]
Free PMC Article
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