Artikel
Characterization of genetic alterations associated with glioblastoma recurrence using next generation gene panel sequencing
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Autoren
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Angela Zacher
- Heinrich Heine University Düsseldorf, Institute of Neuropathology, Düsseldorf, Germany
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Kerstin Kaulich
- Heinrich Heine University Düsseldorf, Institute of Neuropathology, Düsseldorf, Germany
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Stefanie Stepanow
- Heinrich Heine University Düsseldorf, Center for Biological and Medical Research, Düsseldorf, Germany
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Marietta Wolter
- Heinrich Heine University Düsseldorf, Institute of Neuropathology, Düsseldorf, Germany
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Bastian Malzkorn
- Heinrich Heine University Düsseldorf, Institute of Neuropathology, Düsseldorf, Germany
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Karl Köhrer
- Heinrich Heine University Düsseldorf, Center for Biological and Medical Research, Düsseldorf, Germany
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Marcel Kamp
- Heinrich Heine University Düsseldorf, Department of Neurosurgery, Düsseldorf, Germany
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Michael C. Sabel
- Heinrich Heine University Düsseldorf, Department of Neurosurgery, Düsseldorf, Germany
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Guido Reifenberger
- Heinrich Heine University Düsseldorf, Institute of Neuropathology, Düsseldorf, Germany
| Veröffentlicht: | 14. September 2016 |
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Gliederung
Text
Introduction: The genetic alterations driving glioblastoma recurrence following treatment with radiochemotherapy are still incompletely understood. Previous studies have implicated various pathomechanisms linked e.g. to deficient mismatch repair and aberrant activation of different signaling pathways.
Objectives: Our study aims to characterize genetic alterations in pairs of primary (pre-treatment) and recurrent (post-treatment) glioblastomas using next generation sequencing (NGS).
Materials & Methods: We developed customized glioma gene panels for NGS analysis based on the Ion PGM and Ion Proton platforms [1]. Using this technology, we sequenced pairs of primary and recurrent glioblastomas from to date 46 patients. Sequence variants were detected using the variantCaller Plugin (Life Technologies) and further analyzed with the open source software tool ANNOVAR [2]. The NextGENe® v.2.3.4 software (SoftGenetics) was used to characterize copy number changes. All tumors were additionally investigated for MGMT promoter methylation. Relevant clinical parameters of the patients including survival data were retrieved and correlated to the molecular findings.
Results: In all instances, we detected shared mutations between primary and recurrent glioblastomas from individual patients indicating clonal development. These included known driver mutations like TERT promoter mutation, PTEN mutation, TP53 mutation and EGFR amplification. The fraction of private mutations was higher in the recurrent as compared to the primary tumors. Many newly appearing mutations in recurrent tumors were C>T (G>A) transitions compatible with temozolomide-induced mutations. Newly acquired mutations targeted a variety of different genes confirming that different pathomechanisms may contribute to glioblastoma recurrence.
Conclusion: NGS analysis of paired primary and recurrent glioblastomas revealed evidence for clonal selection during tumor progression and emergence of novel mutations targeting different genes. In depth analyses of the complex mutational data sets and correlation with clinical factors is ongoing to characterize relevant genes and pathways driving glioblastoma recurrence.
References
- 1.
- Zacher A, Kaulich K, Stepanow S, Wolter M, Köhrer K, Felsberg J, Malzkorn B, Reifenberger G. Molecular diagnostics of gliomas using next generation sequencing of a glioma-tailored gene panel. Brain Pathol. 2016 Feb 25. DOI: 10.1111/bpa.12367
- 2.
- Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010 Sep;38(16):e164. DOI: 10.1093/nar/gkq603
