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The occurrence of early-onset breast cancer (EOBC) has been associated with germline mutations in the BRCA1 and BRCA2 genes. The first aim of this thesis was to evaluate the frequency and distribution of mutations in these genes, in a group of Cypriot women diagnosed with EOBC. Pathogenic mutations were identified in 6 of the 26 unrelated patients. This study supports a strong correlation between the early onset breast cancer phenotype and the presence of pathogenic BRCA1/2 mutations. It is of interest that pathogenic mutations were detected in patients without a family history of the disease. Based on these results, we recommend that BRCA1/2 screening should be offered to patients with a diagnosis of EOBC irrespective of their family history. The known breast cancer susceptibility genes explain only about 5% of breast cancer cases. Thus, it is likely that other breast cancer susceptibility genes exist. The second aim of the present thesis was to assess whether alterations in DNA repair genes modify breast cancer risk in the Cypriot population. Towards this objective, blood samples were collected and genomic DNA isolated from 1109 Cypriot female breast cancer patients diagnosed between 40-70 years old, and from 1177 age-matched healthy female controls. A total of 79 single nucleotide polymorphisms (SNPs) were genotyped in all samples. Significant associations with breast cancer risk were observed for eight of the SNPs studied. Five SNPs in the BRCA2, MRE11A, MUS81, PBOV1 and XRCC1 genes, were associated with an increased risk for breast cancer, while two SNPs in the NBS1 gene and one SNP in the MRE11A gene appeared to be associated with reduced risk for the disease. The data from this study support the hypothesis that genetic variants in DNA repair genes influence breast cancer risk and provides further evidence for the existence of a polygenic model for breast cancer.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of requirements for the degree of Master of Science. Johannesburg, 2016. / The Organic Cation Transporter 2 (OCT2) gene is responsible for facilitating the transport of cationic compounds, which include both endogenous substrates and clinical drugs. Single nucleotide polymorphisms (SNPs) within this gene were extensively explored in the South African black population as little research has been conducted on these individuals so far. We sequenced the OCT2 promoter region of 10 DNA samples from the South African black population and identified four SNPs and one INDEL. We performed a luciferase assay to determine their effects on gene expression and we found two variants (rs59695691 and rs138765638) that showed a statistically significant change in luciferase expression suggesting that they may be associated with a change in OCT2 regulatory function. We also indentified thirteen SNPs and two INDELs within the OCT2 promoter region, and nine SNPs within the OCT2 coding region through analysing various South African population studies. These variations could affect both gene expression and protein function. These findings help contribute to filling the gap pertaining to OCT variation in South African populations. / LG2017

The potential phenotypic effects of synonymous SNPs (sSNPs) have long been overlooked. Although several sSNPs are no longer thought to be silent, no one has identified which sSNPs may contribute to phenotypic variation on a genome-wide scale. sSNPs that cause a change in codon-usage frequency or mRNA secondary structures may alter translational and protein folding kinetics. In addition, sSNPs that alter splice-site consensus sequences may cause aberrant slicing, which could change the protein product. A sSNP that contributes to any of these molecular mechanisms may thus alter protein structure and function. To computationally identify sSNPs with a potential impact, SynSNP was created. SynSNP is a text-based tool written in Python. All sSNPs published within dbSNP are first identified. SynSNP uses established bioinformatics tools to determine which of the sSNPs may potentially result in a molecular effect. The potentially functional sSNPs are then assessed to determine whether any have previously been associated with a trait or disease in genome-wide association studies (GWAS) and/or occur within genes known to be associated with disease in OMIM (Online Mendelian Inheritance in Man). Of the 90,102 identified sSNPs, 21,086 (23.4%) were predicted to potentially have a functional impact, through one or more of the three molecular mechanisms investigated. Of the sSNPs predicted to potentially have a functional impact, 14 (0.07%) had previously been associated with a trait or disease in GWAS. A subset of 4,057 (19.2%) of the potentially functional sSNPs were within genes known to be associated with disease in OMIM. Only six (0.03%) of the potentially functional sSNPs had previously been associated with a trait or disease in GWAS and occurred within genes known to be associated with disease in OMIM. SynSNP could be developed further to aid the discovery of more sSNPs with a potential functional impact. A significant proportion of sSNPs may have a functional impact and their potential role in disease should therefore not be underestimated or neglected.

A research report submitted to the faculty of health science, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of MSC MED pharmaceutical affairs / MT2017

Amendements: leaves 252-254. Copies of author's previously published articles inserted. Bibliography: leaves 226-251. The CYP2C19 and CYP2D6 genetic polymorphisms control the oxidative metabolism of many different drug classes. Populations are separated into groups of extensive metabolisers (EM), poor metabolisers (PM), and in the case of CYP2D6, ultra-rapid metabolisers (UM). In vitro studies using human liver microsomes were conducted to examine the kinetics of the oxidative metabolism of flunitrazepam, and which CYP450 enzymes mediate the oxidative metabolism of flunitrazepam, (S)-mephenytoin and proguanil.

Graduation date: 1984

Single nucleotide polymorphisms (SNPs) are the most common DNA polymorphisms in plant and animal genomes. SNPs were identified in the allele sequences of up to 12 sunflower (Helianthus annuus L.) genotypes for a genome-wide sample of 81 loci originally mapped using restriction fragment length polymorphism (RFLP) markers. The RFLP loci anchor a dense RFLP linkage map and second-generation linkage maps constructed using simple sequence repeats and other high-throughput DNA markers. The goal of this study was to develop high-throughput SNP markers for the cDNA-RFLP loci for linkage mapping, diversity analysis, and molecular breeding and genomics research. The specific objectives were to: (i) develop FP-TDI or fluorescent primer-extension SNP assays for the cDNA-RFLP loci; (ii) validate the SNP markers by screening 12 sequenced (reference) genotypes; and (iii) assess the utility and polymorphism rate of the SNP markers across a genetically diverse panel of unsequenced wild and domesticated sunflower genotypes. SNP markers were successfully developed for 44 of the targeted 49 cDNA-RFLP loci. Thirty-one of the SNP markers were further selected for a diversity analysis across a genetically diverse panel of wild and domesticated sunflower genotypes. The mean heterozygosity (H) score for the loci was 0.41, which nears the maximum H score of 0.5 for biallelic markers. SNPs in this study exhibited polymorphism rates close to those of RFLP and SSR markers in inbred sunflower lines. / Graduation date: 2004

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 77-109). Also available in print.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences