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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Mutational profiling of kinases in glioblastoma

Authors: Fonnet E Bleeker, Simona Lamba, Carlo Zanon, Remco J Molenaar, Theo JM Hulsebos, Dirk Troost, Angela A van Tilborg, W Peter Vandertop, Sieger Leenstra, Cornelis JF van Noorden, Alberto Bardelli

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma.

Methods

Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before. Among those we selected 34 kinase genes for mutation analysis. We also included IDH1, IDH2, PTEN, TP53 and NRAS, genes that are known to be mutated at considerable frequencies in glioblastoma. In total, 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high-grade glioma (HGG) cell lines were sequenced.

Results

Our mutation analysis led to the identification of 148 non-synonymous somatic mutations, of which 25 have not been reported before in glioblastoma. Somatic mutations were found in TP53, PTEN, IDH1, PIK3CA, EGFR, BRAF, EPHA3, NRAS, TGFBR2, FLT3 and RPS6KC1. Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K-AKT pathway.

Conclusions

The knowledge that at least 50% of glioblastoma tumors display mutational activation of the PI3K-AKT pathway should offer new opportunities for the rational development of therapeutic approaches for glioblastomas. However, due to the development of resistance mechanisms, kinase inhibition studies targeting the PI3K-AKT pathway for relapsing glioblastoma have mostly failed thus far. Other therapies should be investigated, targeting early events in gliomagenesis that involve both kinases and non-kinases.
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Metadata
Title
Mutational profiling of kinases in glioblastoma
Authors
Fonnet E Bleeker
Simona Lamba
Carlo Zanon
Remco J Molenaar
Theo JM Hulsebos
Dirk Troost
Angela A van Tilborg
W Peter Vandertop
Sieger Leenstra
Cornelis JF van Noorden
Alberto Bardelli
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-718

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