Browsing by Author "Kalideen, Kusha"

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    Elucidation of the occurrence of extracolonic cancers in Lynch syndrome
    (2008) Kalideen, Kusha; Ramesar, R
    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.
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    Novel CYP2E1 haplotype identified in a South African cohort
    (2014) Heathfield, Laura J; Dalvie, Shareefa; Kalideen, Kusha; Dandara, Collet
    Alcohol abuse accounts for approximately 2.5 million deaths annually and is the third highest risk factor for disease and disability. Alcohol is metabolised by polymorphic enzymes and the status of an individual with respect to alcohol metabolising enzymes may have forensic relevance in post-mortems. Baseline frequencies of gene variants involved in alcohol metabolism need to be established to aid the identification of suitable population-specific polymorphisms to genotype during molecular autopsies. The principal alcohol metabolising enzymes include alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and cytochrome P450 2E1 (CYP2E1). Six single nucleotide polymorphisms (SNPs) – rs1229984G>A and rs2066702C>T in ADH1B, rs671G>A in ALDH2, and rs3813867G>C, rs2031920C>T and rs6413432T>A in CYP2E1 – were genotyped in 150 individuals from four South African populations: Xhosa, Zulu, South African white and South African coloured. Allele frequencies for each SNP in the four population groups were 0–10% for rs1229984A, 2–12% for rs2066702T, 0–2% for rs671A, 1–4% for rs3813867C, 0–1% for rs2031920T and 3–15% for rs6413432A. Haplotype analysis revealed a novel combination of three SNPs in CYP2E1 whose effects on alcohol metabolism need further investigation. Establishment of baseline frequencies adds to our knowledge of genetic variation in alcohol metabolising enzymes and additional research is required to determine the functional significance of this novel CYP2E1 haplotype.