Abstract | Background: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma patients. Glioblastoma without hypermethylated MGMT promoter is largely resistant to treatment with temozolomide. These patients are in particular need of new treatment approaches, which are offered by biomarker-driven clinical trials with targeted drugs based on molecular characterization of individual tumors. Methods: In preparation for an upcoming clinical study, a comprehensive molecular profiling approach was undertaken on tissues from 43 glioblastoma patients harboring an unmethylated MGMT promoter at diagnosis. The diagnostic pipeline covered various levels of molecular characteristics, including whole-exome sequencing, low-coverage whole-genome sequencing, RNA sequencing, as well as microarray-based gene expression profiling and DNA methylation arrays. Results: Complex multilayer molecular diagnostics were feasible in this setting with a median turnaround time of 4-5 weeks from surgery to the molecular tumor board. In 35% of cases, potentially relevant therapeutic decisions were derived from the data. Alterations were most frequently found in receptor tyrosine kinases, members of the phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin and mitogen-activated protein kinase pathway as well as cell cycle control and p53 regulation cascades. Individual tumors harbored clonal alterations such as oncogenic fusions of tyrosine kinases which constitute promising targets for targeted therapies. A prioritization algorithm is proposed to allocate patients with multiple targets to the potentially best treatment option. Conclusion: With this feasibility study, a comprehensive molecular profiling approach for patients with newly diagnosed glioblastoma harboring an unmethylated MGMT promoter is presented. Analyses in this pilot cohort serve as a basis for trials based on targetable alterations and on the question of allocation of patients to the best treatment arm.
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Authors | Elke Pfaff, Tobias Kessler, Gnana Prakash Balasubramanian, Anne Berberich, Daniel Schrimpf, Antje Wick, Jürgen Debus, Andreas Unterberg, Martin Bendszus, Christel Herold-Mende, David Capper, Irini Schenkel, Andreas Eisenmenger, Susan Dettmer, Benedikt Brors, Michael Platten, Stefan M Pfister, Andreas von Deimling, David T W Jones, Wolfgang Wick, Felix Sahm |
Journal | Neuro-oncology
(Neuro Oncol)
Vol. 20
Issue 6
Pg. 826-837
(05 18 2018)
ISSN: 1523-5866 [Electronic] England |
PMID | 29165638
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Biomarkers, Tumor
- Tumor Suppressor Proteins
- DNA Modification Methylases
- MGMT protein, human
- DNA Repair Enzymes
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Topics |
- Algorithms
- Biomarkers, Tumor
(genetics)
- Brain Neoplasms
(diagnosis, genetics)
- DNA Methylation
- DNA Modification Methylases
(genetics)
- DNA Repair Enzymes
(genetics)
- Feasibility Studies
- Female
- Follow-Up Studies
- Gene Expression Regulation, Neoplastic
- Glioblastoma
(diagnosis, genetics)
- High-Throughput Nucleotide Sequencing
- Humans
- Male
- Middle Aged
- Pilot Projects
- Polymorphism, Single Nucleotide
- Prognosis
- Promoter Regions, Genetic
- Tumor Suppressor Proteins
(genetics)
- Exome Sequencing
- Whole Genome Sequencing
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