This thesis sought to define deletions of chromosome lOin sporadic colorectal adenocarcinoma and determine their role in colorectal tumorigenesis. This thesis has shown a region of frequent loss of heterozygosity (LOH) in the region lOql1-21 centring on the marker D10S1790 at lOq21 suggesting this is the most likely locus of a putative tumour suppressor gene in this region. It has also been shown that LOH at this marker (D10S1790) is significantly associated with earlier presentation of patients. Analysis of adenomas revealed a low frequency of LOH in this region with only two of nine severely dysplastic adenomas showing LOH and none of those with mild or moderate dysplasia. This suggests that loss of the putative tumour suppressor gene at this locus is a late event in colorectal tumorigenesis. Furthermore, deletions at the chromosome 17 locus containing the known tumour suppressor gene, pS3, were examined together with pS3 expression by immunohistochemistry, which are also known to occur late in colorectal tumorigenesis. The frequency of LOH at the pS3 locus as well as pS3 expression were similar to previous studies and there was no significant association with losses at lOq suggesting that loss of a putative tumour suppressor gene at 10q occurs independently of loss of p53 function. LOH at lOq21 was also found not to be associated with LOH at the APe gene locus on 5q21-22 which occurs in up to 50% of sporadic colorectal adenocarcinomas. This thesis suggests that loss of the putative tumour suppressor genets) on lOq provides a selective advantage for clonal expansion in the somatic evolutionary process of colorectal tumorigenesis. Elucidation of the tumour suppressor genets) at this site will further help our understanding of the series of genetic mutations that occur in the evolution of colorectal cancer and will contribute to the efforts in the prevention, early detection and treatment of this prevalent disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:421667 |
| Date | January 2005 |
| Creators | Fawole, Adeshina Sergei |
| Publisher | Keele University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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