title: PI3 kinase mutations and mutational load as poor prognostic markers in diffuse glioma patients.
abstract: BACKGROUND
  Recent advances in molecular diagnostics allow diffuse gliomas to be classified based on their genetic changes into distinct prognostic subtypes. However, a systematic analysis of all molecular markers has thus far not been performed; most classification schemes use a predefined and select set of genes/molecular markers. Here, we have analysed the TCGA dataset (combined glioblastoma (GBM) and lower grade glioma (LGG) datasets) to identify all prognostic genetic markers in diffuse gliomas in order to generate a comprehensive classification scheme.
  
  
  RESULTS
  Of the molecular markers investigated (all genes mutated at a population frequency >1.7 % and frequent chromosomal imbalances) in the entire glioma dataset, 57 were significantly associated with overall survival. Of these, IDH1 or IDH2 mutations are associated with lowest hazard ratio, which confirms IDH as the most important prognostic marker in diffuse gliomas. Subsequent subgroup analysis largely confirms many of the currently used molecular classification schemes for diffuse gliomas (ATRX or TP53 mutations, 1p19q codeletion). Our analysis also identified PI3-kinase mutations as markers of poor prognosis in IDH-mutated + ATRX/TP53 mutated diffuse gliomas, median survival 3.7 v. 6.3 years (P = 0.02, Hazard rate (HR) 2.93, 95 % confidence interval (CI) 1.16 - 7.38). PI3-kinase mutations were also prognostic in two independent datasets. In our analysis, no additional molecular markers were identified that further refine the molecular classification of diffuse gliomas. Interestingly, these molecular classifiers do not fully explain the variability in survival observed for diffuse glioma patients. We demonstrate that tumor grade remains an important prognostic factor for overall survival in diffuse gliomas, even within molecular glioma subtypes. Tumor grade was correlated with the mutational load (the number of non-silent mutations) of the tumor: grade II diffuse gliomas harbour fewer genetic changes than grade III or IV, even within defined molecular subtypes (e.g. ATRX mutated diffuse gliomas).
  
  
  CONCLUSIONS
  We have identified PI3K mutations as novel prognostic markers in gliomas. We also demonstrate that the mutational load is associated with tumor grade. The increase in mutational load may partially explain the increased aggressiveness of higher grade diffuse gliomas when a subset of the affected genes actively contributes to gliomagenesis and/or progression.
authors.affiliation: Department of Neurology, Erasmus MC, Room Be 430A, POBox 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Kaspar
authors.initials: K
authors.lastname: Draaisma
authors.affiliation: Department of Neurology, Erasmus MC, Room Be 430A, POBox 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Maarten M J
authors.initials: MM
authors.lastname: Wijnenga
authors.affiliation: Department of Neurology, Erasmus MC, Room Be 430A, POBox 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Weenink
authors.affiliation: Department of Neurology, Erasmus MC, Room Be 430A, POBox 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Ya
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Medical Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.affiliation: Department of Neurosurgery, UMC Utrecht, Utrecht, Netherlands.|Department of Human Genetics, University of Liège, Liège, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Robe
authors.affiliation: Department of Neurology, Erasmus MC, Room Be 430A, POBox 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.affiliation: Department of Neurology, Erasmus MC, Room Be 430A, POBox 2040, 3000 CA, Rotterdam, The Netherlands. p.french@erasmusmc.nl.
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005910:Glioma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D007521:Isocitrate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein