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Gliosarcoma Is Driven by Alterations in PI3K/Akt, RAS/MAPK Pathways and Characterized by Collagen Gene Expression Signature

Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland
Laboratory of Bioinformatics, Nencki Institute of Experimental Biology, Warsaw 02-093, Poland
Department of Neurosurgery, Institute of Psychiatry and Neurology, Warsaw 02-957, Poland
Department of Pathology, The Children’s Memorial Health Institute, Warsaw 04-730, Poland
Neurosurgical Research, University Clinics, 80539 LMU Munich, Germany
Institute of Neuropathology, University Medical Center, 20251 Hamburg-Eppendorf, Germany
Research Institute Children’s Cancer Center Hamburg, 20251 Hamburg, Germany
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, 69120 Heidelberg, Germany
Author to whom correspondence should be addressed.
Cancers 2019, 11(3), 284;
Received: 4 February 2019 / Revised: 18 February 2019 / Accepted: 19 February 2019 / Published: 27 February 2019
Gliosarcoma is a very rare brain tumor reported to be a variant of glioblastoma (GBM), IDH-wildtype. While differences in molecular and histological features between gliosarcoma and GBM were reported, detailed information on the genetic background of this tumor is lacking. We intend to fill in this knowledge gap by the complex analysis of somatic mutations, indels, copy number variations, translocations and gene expression patterns in gliosarcomas. Using next generation sequencing, we determined somatic mutations, copy number variations (CNVs) and translocations in 10 gliosarcomas. Six tumors have been further subjected to RNA sequencing analysis and gene expression patterns have been compared to those of GBMs. We demonstrate that gliosarcoma bears somatic alterations in gene coding for PI3K/Akt (PTEN, PI3K) and RAS/MAPK (NF1, BRAF) signaling pathways that are crucial for tumor growth. Interestingly, the frequency of PTEN alterations in gliosarcomas was much higher than in GBMs. Aberrations of PTEN were the most frequent and occurred in 70% of samples. We identified genes differentially expressed in gliosarcoma compared to GBM (including collagen signature) and confirmed a difference in the protein level by immunohistochemistry. We found several novel translocations (including translocations in the RABGEF1 gene) creating potentially unfavorable combinations. Collected results on genetic alterations and transcriptomic profiles offer new insights into gliosarcoma pathobiology, highlight differences in gliosarcoma and GBM genetic backgrounds and point out to distinct molecular cues for targeted treatment. View Full-Text
Keywords: gliosarcoma; glioblastoma; transcriptome; PI3K/Akt; RAS/MAPK; mutation; collagen gliosarcoma; glioblastoma; transcriptome; PI3K/Akt; RAS/MAPK; mutation; collagen
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Wojtas, B.; Gielniewski, B.; Wojnicki, K.; Maleszewska, M.; Mondal, S.S.; Nauman, P.; Grajkowska, W.; Glass, R.; Schüller, U.; Herold-Mende, C.; Kaminska, B. Gliosarcoma Is Driven by Alterations in PI3K/Akt, RAS/MAPK Pathways and Characterized by Collagen Gene Expression Signature. Cancers 2019, 11, 284.

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