Mutational profiling of kinases in glioblastoma

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• 作者：Fonnet E Bleeker (4) (5) (6)
  Simona Lamba (4)
  Carlo Zanon (4) (7)
  Remco J Molenaar (8)
  Theo JM Hulsebos (9)
  Dirk Troost (10)
  Angela A van Tilborg (10) (11)
  W Peter Vandertop (12) (5)
  Sieger Leenstra (13) (14)
  Cornelis JF van Noorden (8)
  Alberto Bardelli (15) (4)
  
  4. Department of Oncology ; University of Torino ; SP 142 ; Km 3.95 ; Candiolo ; Torino ; 10060 ; Italy ; Candiolo Cancer Institute 鈥?FPO ; IRCCS ; Candiolo ; Torino ; Italy
  5. Neurosurgical Center Amsterdam ; Location Academic Medical Center ; Meibergdreef 9 ; 1105 ; AZ ; Amsterdam ; The Netherlands
  6. Department of Clinical Genetics ; Academic Medical Center and University of Amsterdam ; Meibergdreef 9 ; 1105 ; AZ ; Amsterdam ; The Netherlands
  7. Neuroblastoma Laboratory ; Pediatric Research Institute ; Fondazione Citt脿 della Speranza ; Corso Stati Uniti 4 ; 35127 ; Padua ; Italy
  8. Department of Cell Biology and Histology ; Academic Medical Center ; University of Amsterdam ; Meibergdreef 9 ; 1105 ; AZ ; Amsterdam ; The Netherlands
  9. Department of Neurogenetics ; Academic Medical Center ; University of Amsterdam ; Meibergdreef 9 ; 1105 ; AZ ; Amsterdam ; The Netherlands
  10. Department of Neuropathology ; Academic Medical Center ; University of Amsterdam ; Meibergdreef 9 ; 1105 ; AZ ; Amsterdam ; The Netherlands
  11. Department of Pathology ; UMC St. Radboud ; Geert Grooteplein-Zuid 10 ; 6525 ; GA ; Nijmegen ; The Netherlands
  12. Neurosurgical Center Amsterdam ; Location Vrije Universiteit Medical Center ; De Boelelaan 1117 ; 1081 ; HZ ; Amsterdam ; The Netherlands
  13. Department of Neurosurgery ; St. Elisabeth Ziekenhuis ; Hilvarenbeekse Weg 60 ; 5022 ; GC ; Tilburg ; The Netherlands
  14. Department of Neurosurgery ; Erasmus Medical Center ; 鈥檚-Gravendijkwal 230 ; 3015 ; CE ; Rotterdam ; The Netherlands
  15. FIRC Institute of Molecular Oncology ; Via Adamello 16 ; 20139 ; Milan ; Italy
  
• 关键词：Glioblastoma ; Kinase ; Gene ; Molecular ; Mutation ; PI3K ; AKT
• 刊名：BMC Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：14
• 期：1
• 全文大小：607 KB
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• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

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.