Comparative expression analysis of brain tumours to identify biomarkers and therapeutic targets

The prognostication of human gliomas has seen significant changes over the last 10 years. The identification of mutations in two isocitrate dehydrogenase genes, IDH1 and IDH2, in gliomas [1] was a major discovery, leading to a biomarker-defined glioma classification, IDH and ATRX-mutant astrocytomas and glioblastomas and IDH-mutant 1p/19q codeleted oligodendrogliomas [2]. The clinical value of molecular subtyping of Idh-wildtype glioblastoma instead had limited clinical impact [3,4]. The only prognostic biomarker in GBM is the methylation of MGMT but it has no diagnostic value [5]. To identify biomarkers with diagnostic and/or prognostic value, we chose a hypothesis-generating approach by comparing mouse models with genetically defined mutations arising from the neurogenic zone of the developing or adult brain. These models develop distinct brain tumour phenotypes. Described in the first part of this thesis, we compared two biologically and histologically diverse tumours; diffuse glioma and primitive neuroectodermal tumours. We identified a highly differentially regulated miRNA, miR-449a and its downstream target, Gpr158. MiR-449a is highly expressed in the most malignant form of human adult glioma, glioblastoma and much less in the less aggressive forms, astrocytoma and oligodendroglioma. The second part of the thesis describes the role of IDH1R132H mutation, a very frequent mutation in WHO grade II-III gliomas, in delaying tumourigenesis and its role in sensitising tumour cells to endoplasmic reticulum stress. In a mouse model of intrinsic gliomas, tumours harbouring the Idh1R132H mutation were directly compared to Idh1 wildtype counterparts, both in the background of Pten and p53 mutation. In our comparative gene expression approach, we identified miR-183 is a highly differentially regulated miRNA and contributes to the cell response to endoplasmic reticulum stress. This work demonstrates that mouse models are ideal to discover biologically relevant biomarkers of glioma malignancy in humans and to identify potential therapeutic targets