Genetic and epigenetic changes in CNS cancers

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Shinawi, Thoraia M (2015). Genetic and epigenetic changes in CNS cancers. University of Birmingham. Ph.D.

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Abstract

Cancer is a result of multiple genetic and epigenetic alterations that are acquired during tumour formation and progression. The development of cost-effective high-throughput technologies has positively contributed to the field of cancer research to identify cancerassociated genes, in addition to diagnostic and prognostic markers. Using the most recent Illumina Infinium HumanMethyaltion450K BeadChip, this work has identified 23 genes that were significantly and differentially hypermethylated in short-term survivor (STS) glioblastoma patients and showed an association with poor prognosis. Interestingly, \(NR2F2\) showed hypermethylation across multiple CpG loci and was significantly correlated with poor survival. In addition, the work has identified a subset of long-term survivors (LTS) that showed high DNA hypermethylation across many CpG loci indicating the presence of CIMP\(^+\).
The other methylation study has identified 7 genes (\(EOMES\), \(WDR69\), \(MIR125B1\), \(DZIP1\), \(SOX1\), \(PHOX2B\) and \(PRDM13\)) that were differentially hypermethylated in breast cancer brain metastasis (BCBM) tumours compared to non-metastatic breast tumours. These genes also showed hypermethylation in the paired breast tumours and BCBM samples, signifying the importance of the 7 genes in the development of brain metastasis in the early stages. Loss of expression of \(DZIP1\), \(PRDM13\) and \(PHOX2B\) was significantly associated with poor patient survival, indicating their potential as prognostic markers for BCBM patients.
Whole exome sequencing (WES) analysis of sporadic non-\(NF2\) vestibular schwannoma was disappointing and was not able to identify somatic mutations in the novel genes involved in schwannoma formation. However, the identification of novel deleterious mutations in the \(NF2\) gene confirmed the validation of WES to identify cancer-associated variants.
This study has used the most recent and developed high-throughput technologies to identify candidate genes that were genetically or epigenetically altered in a range of CNS tumours.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):