Abstract
Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (−10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/−10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.
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Abbreviations
- AII:
-
Diffuse astrocytoma WHO grade II
- AAIII:
-
Anaplastic astrocytoma WHO grade III
- AOIII:
-
Anaplastic oligodendroglioma WHO grade III
- AOAIII:
-
Anaplastic oligoastrocytoma WHO grade III
- ATRX:
-
ATP-dependent X-linked helicase
- BRAF:
-
v-raf murine sarcoma viral oncogene homolog B1
- CDK:
-
Cyclin-dependent kinase
- CGH:
-
Comparative genomic hybridization
- CIC:
-
Drosophila homolog of capicua
- EGFR:
-
Epidermal growth factor receptor
- GB IV:
-
Glioblastoma WHO grade IV
- gCIMP:
-
Glioma CpG island methylator phenotype
- GGN:
-
German Glioma Network
- GO:
-
Gene ontology
- IDH:
-
Isocitrate dehydrogenase
- KPS:
-
Karnofsky performance score
- MAPK:
-
Mitogen-activated protein kinase
- MDM:
-
Murine double minute
- MGMT:
-
O6-methylguanine DNA methyltransferase
- OII:
-
Oligodendroglioma WHO grade II
- OAII:
-
Oligoastrocytoma WHO grade II
- OS:
-
Overall survival
- PDGFRA:
-
Platelet-derived growth factor receptor-α
- PFS:
-
Progression-free survival
- PTEN:
-
Phosphatase and tensin homolog on chromosome 10
- SOM:
-
Self-organizing map
- TERT:
-
Telomerase reverse transcriptase
- TMZ:
-
Temozolomide
- TP53:
-
Tumor protein p53
- WHO:
-
World Health Organization
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Acknowledgments
This study was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe, grant no. 70-3163-Wi 3) and by the German Cancer Consortium (DKTK). The authors would like to thank the staff at the clinical centers of the German Glioma Network for their great support as well as our patients and their relatives. We also acknowledge Thorsten Wachtmeister, Center for Biological and Medical Research, Heinrich Heine University Düsseldorf, for his support of the Affymetrix chip hybridizations.
Conflict of interest
MiW has received research grants from Acceleron, Actelion, Bayer, Isarna, Merck Serono, MSD, Piqur and Roche, and honoraria for lectures or advisory boards from Celldex, Isarna, Magforce, Merck Serono, MSD and Roche. GR has received research grants from Roche and Meck as well as honoraria for advisory boards or lectures from Merck Serono, Amgen and Roche. TP has received grants for reference pathology from Antisense Pharma and Merck Serono and honoraria for lectures from Roche. US has received honoraria for lectures or advisory boards from GSK, medac and Roche. TM has received honoraria for lectures from medac and Cyberonics and for advisory boards from Novocure. JCT has received honoraria for lectures or advisory boards from Merck Serono, medac and Roche. CHar has received grants for research and advisory board activities from Apogenix and Oncowave. The other authors declare that they have no conflicts of interest.
Funding
This study was funded by the German Cancer Aid (Grant No. 70-3163-Wi 3).
Access to gene expression data
The gene expression data reported in this study are deposited in the gene expression omnibus (GEO) database at http://www.ncbi.nlm.nih.gov/geo/ under accession number GSE61374 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=qhyzsoqmhbibxch&acc=GSE61374).
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M. Weller and R. G. Weber: share first authorship.
H. Binder and G. Reifenberger: share last authorship.
For the German Glioma Network.
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Weller, M., Weber, R.G., Willscher, E. et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol 129, 679–693 (2015). https://doi.org/10.1007/s00401-015-1409-0
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DOI: https://doi.org/10.1007/s00401-015-1409-0