Rees, Michele; (1991) Molecular genetic studies in familial and sporadic colorectal neoplasia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Colorectal carcinogenesis is a multistep process classically characterised by at least four independent genetic events including loss of constitutional heterozygosity on chromosomes 5,17 and 18 and point mutations of the K-ras cellular protooncogene. Because of the ready availability of post-operative material, both premalignant and malignant, adenomatous polyposis coli (APC) provides an ideal source and model for the study of the molecular genetic events involved in colorectal tumour progression. This study has, therefore, involved a detailed investigation of these phenomena and an attempt to correlate them with respect to the stage of tumour development. Loss of heterozygosity in tumorigenesis is thought to signify involvement of tumour suppressor sequences at those loci and was therefore investigated using polymorphic DNA probes specific for the regions of the genome previously implicated in progression towards the malignant phenotype. Included in this survey was investigation of the status of the tumour suppressor genes p53 and DCC and that of the putative tumour suppressor gene MCC. The frequency of losses seen was generally in agreement with the results previously published with chromosome 17 and 18 losses being much more frequent in carcinomas than in adenomas. The frequency of K-ras point mutations was approximately seven-fold lower in adenomas than in carcinomas signifying that it is an early event in colorectal carcinogenesis but that it is not the initiating one. The nature of K-ras mutations was also studied by direct sequencing of the first exon and revealed the most common base change to be a G to A transition at position 2 of codon 12 representing the substitution of aspartic acid for glycine. To date little evidence has been presented for the occurrence of chromosome 5 allele loss in APC-derived adenomas. This study illustrates that such loss, though infrequent in the general APC population, is significantly higher in a subset of patients who seemingly represent "new mutations" in that they have no prior family history of the disease. Using a panel of locus-specific hypervariable minisatellite probes the possibility of non-paternity was ruled out. These patients, therefore, represent true "new mutations" and appear to exhibit a more aggressive form of the disease characterised by earlier onset of malignancy. These observations are possibly indicative of genetic heterogeneity at the APC locus.

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