Molecular and Clinical Implications of IDH1 and EGFR Mutations in Gliomas

To improve the clinical outcome of glioma patients, there is considerable need to discover novel treatment options for patients. This firstly requires better understanding of the molecular mechanism of the driver mutations in each subgroup of gliomas. In this thesis, we report on the creation of in vitro and in vivo model systems for understanding the function of driver mutation IDH1 in LGG. We further studied the molecular pathways affected by driver mutations in LGG and GBM. For both IDH1 and EGFR mutations, we identified novel binding partners. Surgical resection of recurrent GBMs is performed only in a minority of patients and treatment strategies using targeted-therapy are heavily dependent on the molecular data of primary tumors. In this thesis, we showed that most of EGFR amplification in the primary tumor was retained at tumor recurrence therefore indicates that molecular data obtained in the primary tumor can be used to predict the EGFR status of the recurrent tumor. The final chapter of this thesis describes gene-expression analysis of samples included in the EORTC22033-26033 clinical trial. We showed that previ- ously de ned intrinsic glioma subtypes, subtypes based on unsupervised expression analysis of gene expression data, are prognostic for progression-free survival in EORTC22033-26033 clinical trial samples.

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