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Elucidation of the occurrence of extracolonic cancers in Lynch syndrome

By Kusha Kalideen

Abstract

Includes abstract.Includes bibliographical references (leaves 126-147).Lynch Syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) (OMIM #120435), is a familial disorder resulting from mutations within DNA MMR genes. Effective surveillance, diagnosis and treatment of the disorder is complicated due to the phenotypic and genetic heterogeneity of lynch syndrome, which exhibits an autosomal dominant mode of inheritance. Determine the molecular pathology of extracolonic cancers in Lynch syndrome and to elucidate whether or not the occurrence of these extracolonic cancers are a direct result of the mismatch repair deficiency. First, a modifier study was performed assessing the effect of a variant within the DNA MMR gene hMLH1 in a cohort of individuals predisposed to Lynch syndrome in order to examine a potential epistatic effect in the gene. In order to obtain a genetic signature of Lynch associated tumours, germline DNA and corresponding tumour DNA was isolated from Lynch syndrome patients. The genetic material was assessed via a panel of microsatellite rich genes and MS-MLPA. Finally, in silico analyses were undertaken assessing microarray data from microsatellite unstable colorectal and endometrial cancers to characterise novel candidate genes. The modifier study did not prove fruitful as no association was found between the hMLH1 promoter variant and site of cancer in individuals predisposed to Lynch syndrome. An association was observed heterozygous and homozygous variant genotypes and an increased risk of colorectal cancer, regardless of predisposing mutation (p = 0.000181). Two tumour suppressor genes; HIC1 and TIMP3, were found to be methylated in the tumour samples in the germline/tumour tissue study. This study also showed instability of the Erβ gene in the majority of tumour samples. Bioinformatic analysis utilising existing microarray data resulted in common under-expression of four genes and common overexpression in three genes in microsatellite unstable colorectal and endometrial cancers. Further investigation into the modifier study and elucidation of a genetic signature in MMR deficient, MSI cancers. The results obtained in this study contribute to the increasing body of knowledge in the field and the various stages of malignancies should be assessed for a more informative result. Genetic and functional studies should be performed on the information garnered from the bioinformatics analysis. Overall evaluation and molecular classification of Lynch syndrome tumours may guide better diagnosis, surveillance and treatment of those at risk

Topics: Medicine
Publisher: Department of Clinical Laboratory Sciences
Year: 2008
OAI identifier: oai:open.uct.ac.za:11427/3167
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