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).
CONCLUSION: 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.