Molecular characterisation of lower-grade glioma and investigation of its genomic aberrations influencing patient prognosis and therapeutic response

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Copyright: Noor, Humaira
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Abstract
Lower-grade gliomas (LGGs) are tumours of the Central Nervous System affecting young adults aged 17-44 years. The overall survival of LGG patients has not improved significantly over the last 30 years, and new therapeutic approaches are warranted to effectively treat this cancer. In this thesis, I have molecularly characterised a retrospective cohort of LGG specimen from 102 patients, including 29 patients with matched primary and recurrent tumours, in order to identify prognostic biomarkers, molecular subgroups with unfavourable prognosis and investigate their potential as therapeutic targets through pre-clinical studies. Specific hotspot tumour protein 53 (TP53) codon 273 mutations occurred in 33% of astrocytoma, which were associated with significantly improved survival in both univariate (p<0.05) and multivariate analysis (p<0.05). TP53 wildtype tumours were associated with the most unfavourable clinical outcome. Analysis of publicly available LGG datasets validated these findings and elucidated the mechanism of this prognostication involving enhanced chemosensitivity of TP53 codon 273 mutations. Integrated analysis uncovered interactions between Yes-associated protein 1 (YAP1) and TP53 mutation potentially plays a role in inducing this chemosensitivity. In silico analysis identified the over-expression of carbonic anhydrase 12 (CA12) mRNA in the TP53 wildtype astrocytoma sub-group with the most unfavourable prognosis. I attempted to establish LGG patient-derived neurosphere cell lines for in vitro drug efficacy studies with the CA12 inhibitor U-104 combined with temozolomide treatment. Drug efficacy studies were conducted on a panel of TP53 wildtype and TP53 mutant glioblastoma cell lines where U-104 monotherapy, but not combination therapy, was efficacious in both subgroups. U-104 monotherapy also showed efficacy in LGG neurospheres. Molecular characterisation revealed that 72.9% of astrocytomas and 63.2% of oligodendrogliomas followed alternative lengthening of telomere (ALT) mechanism to maintain their telomere lengths. Neither ALT nor telomerase mechanisms were prognostic factors in astrocytoma, while, ALT was a significantly associated with a longer progression-free survival in oligodendroglioma. Cyclin a1 (CCNA1) was identified as a potential ALT-associated gene in the analysis of in-house RNA sequencing data. While CCNA1 methylation was not found to be directly associated with ALT upon investigation, CCNA1 methylation showed a strong trend for association with ALT-associated aberrations in ATRX, and progression-free survival in both the in-house astrocytoma cohort and TCGA dataset. Moreover, CCNA1 methylation levels were significantly associated with increasing astrocytoma grade, and it may be involved in tumour progression and aggressiveness. In conclusion, this thesis identified therapeutically actionable biomarkers, determinant of chemosensitivity, and prevalence of TMMs in LGG.
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Publication Year
2022
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Thesis
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PhD Doctorate
UNSW Faculty
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