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Title: Investigation into cytosine epigenetic state in bladder cancer
Author: Albaz, Alrayan
ISNI:       0000 0004 7651 645X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Bladder cancer is a common malignancy that is best classified into high and low grade disease. Low-grade cancers are indolent in nature but expensive to manage. High-grade cancers can be invasive at diagnosis and have a poor prognosis. Molecular studies suggest high and low grade tumours are biologically distinct. All bladder cancers are characterised by heterogenous cell populations, high mutational burden and can be classified into molecular sub-groups using RNA expression and cell surface markers. Here I have explored these subgroups further and look at heterogenicity in primary muscle invasive bladder cancers (MIBC). Firstly, I extracted different cell populations from fresh MIBC biopsies. I developed protocols to handle these specimens and used flow cytometry to isolate subpopulations. I discovered different cell populations exist, in different fractions, and that this information may reveal tumour subgroups. For example, subpopulations expressing CD44 and CD49f (indicators of a terminally differentiated urothelial subtype) were common and there was often a lack of CD90 cell surface receptor expression (an indicator of the basal differentiated subtype). Secondly, I examined changes in epigenetic traits at cytosine residues to explore the frequency and extent of hydroxymethyl cytosine for the first time in bladder cancer. Using a 450K microarray I identified patterns of change that could affect key carcinogenic genes and could distinguish benign and malignant tissues using 5 methyl and 5 hydroxy methyl cytosine residues. Pathway analysis revealed several biochemical signalling pathways and over 30 genes to have altered cytosine residues. Finally, I validated these epigenetic findings in individual tumours and normal urothelium as well as in subpopulations identified in flow cytometry. Although this research took a modest approach towards addressing queries raised by epigenetic alterations, it could serve as groundwork for future research. These include development of a primary tissue culture technique for malignant urothelial tissues and to identify the least differentiated bladder subpopulations. The genes and pathways identified using the array data should be investigated in further detail using murine models to better understand their role in urothelial carcinomas.
Supervisor: Catto, James Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available