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Title: Colerectal cancer genetics : a study of chromosome 8p tumour suppressor loci and microsatellite instability
Author: Cunningham, Christopher
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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Fourteen chromosome 8 polymorphic loci were analysed for loss of heterozygosity in 119 colorectal cancers selected at random. Loss of heterozygosity was detected in 59.6% (59/99) of informative cases. Markers were of sufficient density to allow the construction of a deletion map which delineated two discrete regions likely to contain tumour suppressor loci. A 4cM region at 8p22-21.3 between markers D8S133 and LPL and a further locus at 8p21-11.2, between markers D8S137 and D8S136, estimated to span some 17cM. Loss of heterozygosity on chromosome 8p was found to be independent of tumour site, Duke's stage, patient age, sex and survival. Analysis of 50 sporadic colorectal adenomas revealed a low frequency of chromosome 8p loss of heterozygosity, suggesting that the tumour suppressor loci are preferentially involved in the later stages of colorectal carcinogenesis. The role of defective DNA mismatch repair in colorectal cancer predisposition has been reported recently. These defects are manifested by microsatellite instability. Such instability was noted in tumour DNA during chromosome 8p loss of heterozygosity studies and the project was extended to investigate this phenomenon. The prevalence of microsatellite instability was determined in 245 colorectal cancers. 16.7% (41/245) displayed replication errors at one or more microsatellite loci, suggesting underlying errors in mismatch repair. Cancers displaying microsatellite instability tended to arise in the proximal colon, maintained nuclear diploidy and were associated with a significantly improved survival. The presence of replication errors was independent of patient age and sex, loss of heterozygosity at chromosomes 5q and 17p and immunohistochemistry for p53 protein. Loss of heterozygosity affecting chromosome 8p and defective DNA mismatch repair are frequent genetic abnormalities in colorectal cancers. This project provides important data localising the putative tumour suppressor genes to two discrete regions on chromosome 8p. This will aid future efforts towards cloning and identifying the genes involved. In addition, the prevalence and clinicopathological features of microsatellite instability have been established, in a large population of unselected colorectal cancers, allowing insight into the involvement of this mechanism in sporadic colorectal carcinogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available