Fonseca, Raquel; (2023) Generation and characterization of a mouse model of IDH mutant astrocytoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

IDH-mutant astrocytomas affect adults in their 20s-40s with an incidence of approximately 5individuals per million annually, i.e., at least 300 new tumours are diagnosed, yearly, in the UK1. These tumours carry mutations in the genes encoding isocitrate dehydrogenase enzyme 1 or 2 (IDH1/2), leading to the accumulation of a new metabolite, 2 hydroxyglutarate (2HG), which affects cell metabolism and causes global DNA hypermethylation, thought to drive neoplastic transformation2. The impact on these individuals’ lives is significant, and there is still uncertainty about prognosis of individual tumours. The generation of Idh-mutant mouse models has failed to recapitulate the formation of gliomas due to unwanted effects during embryonic development3. ATRX is a chromatin regulator which plays an important epigenetic role, depositing histones at heterochromatin and telomeric DNA4. Its loss is associated with genomic and telomeric instability and has been identified as a defining molecular determinant for a large subset of IDH-mutant low-grade gliomas5,6, but its role in tumour initiation and progression is still unclear7,8. We have generated a mouse model that recapitulates features of glioma, expressing human IDH1R132H, the most common form in astrocytomas9. Using this model, we use CRISPR/Cas9 technology to introduce additional genetic alterations, resulting in tumours expressing IDHR132H, p53, ATRX and CDKN2A mutations, i.e., the same mutational profile described in human patients. Moreover, we were able to generate distinct tumour groups with a correspondent mutational signature and compare these groups to evaluate the impact of such profiles in survival and methylation. Overall, despite expressing different mutations in tumour suppressor genes which should impact the tumour behavioural, these tumours did not show significant differences between the distinct groups, probably due to the overriding impact of the mitogen PDFGB, which seemed to mask all the nuances that could be cause by the different combination of genetic mutations in each group. Ultimately, this mouse model represents a robust, effective, and rapid method for induction of tumours with a genetic profile that recapitulates the human counterparts, with strong potential for the study of candidate drugs, drug delivery approaches or new therapeutic strategies.

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