Burghel, George (2011) Inherited and Somatic Genetic factors in Colorectal Cancer Development. PhD thesis, University of Sheffield.
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ABSTRACT Colorectal cancer (CRC) is the 3rd most common cancer and the 4th highest cause of cancer deaths in the world. Genetic factors play a major role in its predisposition, initiation and development. Inherited variants in the CASP8 gene, a key regulator of apoptosis, have a potential yet controversial association with CRC risk. Sporadic CRC develop through different molecular pathways of genomic instabilities and mutations in key cancer driver genes. Classification of sporadic CRC into these molecular pathways has potential implications for diagnosis and treatment and it is an integral part of CRC studies, however, current published research suffers from lack of standardisation. Chromosomal Instability (CIN) drives CRC by affecting cancer driver genes, many of which are still to be identified. This project aimed to: (a) further investigate the role of CASP8 inherited variants in CRC risk, (b) to molecularly classify sporadic CRC tumour DNA samples using standard techniques and definitions, and (c) to identify novel CRC driver genes affected by CIN. A CASP8 promoter in/del variant was genotyped in 1193 CRC cases and 1388 matching controls. The coding region of the CASP8 gene was sequenced in 94 CRC cases to identify potential novel variants and a copy number variant was also investigated. A cohort of 53 paired CRC tumour and normal DNA samples were molecularly classified using standard techniques and definitions. Common aberration analysis was performed on high resolution array comparative genome hybridisation data from 45 chromosomally unstable CRC cases to identify focal minimal common regions (FMCR). CASP8 inherited variants did not significantly affect CRC risk in the investigated cohort. CRC molecular classification confirmed the heterogeneity of sporadic CRC vii and a novel molecular subtype was proposed. FMCR were shown to target cancer related genes and novel CRC driver genes were proposed. Finally, preliminary studies supported the tumour suppressor role of NFKBIA, one of the novel candidate driver genes affected by a deletion FMCR.
|Item Type:||Thesis (PhD)|
|Department:||The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)|
|Deposited By:||Mr George Burghel|
|Deposited On:||09 Dec 2011 16:15|
|Last Modified:||09 Dec 2011 16:15|
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