Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649800
Title: Clinical and molecular genetic studies in familial adenomatous polyposis and colorectal carcinoma
Author: Dunlop, Malcolm Graham
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1991
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Abstract:
One hundred and forty-six sporadic colorectal carcinomas were analysed. Allele loss was demonstrated in 54% of tumours informative at any locus and in 51 (60%) of the 85 tumours where markers closely flanking the apc gene were informative on both sides. apc gene losses were small interstitial deletions (64%), mitotic recombination events (33%) and whole chromosome loss (3%). No correlation of chromosome 5 allele loss and tumour stage, site or ploidy level was noted, suggesting the early involvement of apc in colorectal carcinogenesis. The smallest common region of deletional overlap involved the locus EF5.44. Linkage analyses have not demonstrated any recombinants with this probe and 3 tumours showed deletions extending centromeric to EF5.44 and 4 other tumours demonstrated deletions extending telomeric from that locus with retention of EF5.44 heterozygosity in each case. These data suggest that EF5.44 is within the apc gene itself and are the first 'signpost' to allow isolation of the gene. Sporadic adenomas demonstrated an overall loss of heterozygosity of 29% (19 of 65 informative) at any chromosome 5 locus. The incidence of allele loss in sporadic adenomas was significantly lower than in carcinomas for overall chromosome 5 loss and for loss at each locus. This suggests that apc gene deletion is permissive for tumour progression and is an early, rate-limiting step. Analysis of large DNA fragments at the EF5.44 locus by pulse field gel electrophoresis was carried out using blood leukocytes from 2 patients who were new mutations for FAP. Using normal parents as controls, a rearranged EF5.44 pulse-field fragment was demonstrated in one of these patients. However this evidence was inconclusive and the further lengthy analysis required to confirm and extend this finding are outwith the remit of this project. If confirmed, this finding supports the deletion mapping data and suggests that EF5.44 is less than 500 kilobases from the apc gene, if not within it. This project has mapped a number of DNA probes around the apc gene and allowed the use of these in the clinical setting. Deletion mapping in colorectal neoplasms has demonstrated the consistent and specific involvement of that gene in colorectal carcinogenesis and appears to be permissive for adenoma-carcinoma progression. The demonstration and delineation of small interstitial deletions in malignant tissue have allowed localisation of the apc gene to a very small chromosomal region. This novel means of gene mapping has allowed isolation of a gene involved in the development of one of the most common human malignancies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.649800  DOI: Not available
Share: