Browsing by Author "Van der Merwe, Nicole"

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    CYP2D6 genotyping and use of antidepressants in breast cancer patients : test development for clinical application
    (Springer Verlag, 2012-05) Van der Merwe, Nicole; Bouwens, Christianne S. H.; Pienaar, Rika; Van der Merwe, Lize; Yako, Yandiswa Y.; Geiger, Dieter H.; Kotze, Maritha J.
    Approximately 25 % of clinically important drugs and numerous environmental carcinogens are metabolised by CYP2D6. Variation in the CYP2D6 gene and concomitant use of tamoxifen (TAM) with certain antidepressants may increase recurrence risk in breast cancer patients due to reduced enzyme activity. In this study we determined the appropriateness of adding CYP2D6 genotyping to the breast cancer genetic testing options already available in South Africa, which include BRCA mutation screening and transcriptional profiling to assess estrogen receptor (ER) status. A total of 114 South African breast cancer patients, including 52 Caucasian and 62 Coloured (Mixed ancestry), and 63 Caucasian control individuals were genotyped for the most common inactivating allele (CYP2D6*4, rs3892097) previously identified in the CYP2D6 gene. In the initial validation data set consisting of 25 Caucasian and 62 Coloured patients, the CYP2D6*4 allele frequency was significantly higher in Caucasian compared to Coloured patients (24 % vs. 3 %, p≤0.001), similar to previous findings in the general South African population. Extended CYP2D6 genotyping was subsequently performed in an implementation data set of 27 Caucasian breast cancer patients, to determine the prevalence of depression and use of antidepressants in a clinical setting. A medical history of depression and/or use of antidepressants was reported in 37 % (10/27) of these breast cancer patients genotyped for CYP2D6*4. This translational research study has led to increased awareness among clinicians of the potential benefits of CYP2D6 genotyping to facilitate prevention of cumulative risk in a high-risk genetic subgroup of breast cancer patients considered for concomitant treatment of TAM and antidepressants that may reduce enzyme function. © Springer Science+Business Media, LLC 2012.
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    Development and application of a pathology supported pharmacogenetic test for improved clinical management of South African patients with breast cancer and associated co-morbidities
    (Stellenbosch : Stellenbosch University, 2016-03) Van der Merwe, Nicole; Kotze, Maritha J.; Pienaar, Fredrieka; Janse van Rensburg, Susan; Bezuidenhout, Juanita; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Anatomical Pathology.
    ENGLISH ABSTRACT: Three major challenges in the field of breast cancer have been identified as research priorities for this study. The first is the need to combine genetic testing of high-risk patients with familial breast cancer with pharmacogenetics to reduce recurrence risk in cancer survivors due to drug failure as a consequence of anti-cancer treatment that does not match the patient’s genotype. The second is the delineation of key pathways through which genes implicated in breast cancer and associated co-morbidities can serve as nutritional and drug targets across diagnostic boundaries. The third is the discovery of genetic alterations underlying familial breast cancer not attributed to mutations in the two major tumour suppressor genes, BRCA1 and BRCA2. The study population consisted of 164 breast cancer patients (60 Coloured/Mixed Ancestry and 104 Caucasian), of whom 88 patients were selected from a total of 813 individuals who provided informed consent for inclusion of their data in a genomics database resource generated at the interface between the laboratory and routine clinical practice. In addition, DNA samples of 101 cancer-free individuals above the age of 65 years were available for clinical validation of potentially causative variants in an extended female control group. In the first phase of this study, real-time polymerase chain reaction (PCR) TaqMan© technology was used to confirm the potential value of adding pharmacogenetic testing (CYP2D6 allele 4) to standard immunohistochemistry (IHC)-based breast tumour subtyping complemented by BRCA mutation screening and/or microarray gene profiling in eligible patients. In phase two of the study, common genetic risk factors for cardiovascular disease (CVD) were shown to be significantly associated with earlier age (10 years on average) of breast cancer onset/diagnosis (APOE E4 allele p=0.003; 95% CI: 4-15) and body mass index (BMI) (MTHFR 1298 A>C; p=0.01; 95% CI: 3-14) in patients stratified according to estrogen receptor (ER) status, after adjustment for potential confounders. Age at diagnosis/onset of breast cancer was significantly lower in patients with ER-negative versus ER-positive tumours, after adjustment for ethnicity (p=0.022), while BMI was significantly higher in patiens with ER-positive compared to ERnegative tumours after adjustment for age, ethnicity, and family history of cancer (p=0.035). These findings contributed to the development of an exome pre-screening algorithm (EPA) used in part 3 of this study to select three genetically uncharacterized breast cancer patients for whole exome sequencing (WES) performed in comparison with three ethnically concordant cancer-free controls. WES followed by variant calling using both the standard human genome reference sequence (hg19) and an ethnically concordant major allele reference genome (MARS) revealed a more than 20% discrepancy in the number of gene variants identified in the same samples. After exclusion of a large number of false-positives caused by minor alleles in hg19, two rare missense mutations (<1%) were identified in a family with ER-positive breast cancer: RAD50 R385C and MUC1 Q67E. Three different bioinformatics tools were used to predict functionality and both mutations were confirmed by Sanger sequencing and/or real-time PCR in the Pathology Research Facility (PRF) laboratory. Neither the RAD50 nor the MUC1 missense mutation were identified in the exomes of an unrelated breast cancer patient with triple-negative breast cancer or three population-matched control individuals. This study led to the development of a pathology-supported genetic testing framework for WES beyond the limitations of single-gene BRCA mutation screening in South African breast cancer patients. Our findings support previous WES results indicating that the majority of genetically uncharacterised familial breast cancer may be caused by a combination of low-moderate penetrance mutations exerting their effect in a high-risk environment reflected by high BMI. WES enables identification of genetic risk factors of relevance to both cancer development and tailored therapeutic intervention in a single genetic test.
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    Exome sequencing in a family with luminal-type breast cancer underpinned by variation in the methylation pathway
    (MDPI, 2017-02-22) Van der Merwe, Nicole; Peeters, Armand V.; Pienaar, Fredrieka M.; Bezuidenhout, Juanita; Van Rensburg, Susan J.; Kotze, Maritha J.
    ENGLISH ABSTRACT: Panel-based next generation sequencing (NGS) is currently preferred over whole exome sequencing (WES) for diagnosis of familial breast cancer, due to interpretation challenges caused by variants of uncertain clinical significance (VUS). There is also no consensus on the selection criteria for WES. In this study, a pathology-supported genetic testing (PSGT) approach was used to select two BRCA1/2 mutation-negative breast cancer patients from the same family for WES. Homozygosity for the MTHFR 677 C>T mutation detected during this PSGT pre-screen step was considered insufficient to cause bilateral breast cancer in the index case and her daughter diagnosed with early-onset breast cancer (<30 years). Extended genetic testing using WES identified the RAD50 R385C missense mutation in both cases. This rare variant with a minor allele frequency (MAF) of <0.001 was classified as a VUS after exclusion in an affected cousin and extended genotyping in 164 unrelated breast cancer patients and 160 controls. Detection of functional polymorphisms (MAF > 5%) in the folate pathway in all three affected family members is consistent with inheritance of the luminal-type breast cancer in the family. PSGT assisted with the decision to pursue extended genetic testing and facilitated clinical interpretation of WES aimed at reduction of recurrence risk.
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    "They have put a rope around my neck by bringing me here”: a historical exploration of witchcraft trials in the Transkeian Territories, 1882-1906
    (Stellenbosch : Stellenbosch University, 2021-12) Van der Merwe, Nicole; Fransch, Chet James Paul; Stellenbosch University. Faculty of Arts and Social Sciences. Dept. of History.
    ENGLISH ABSTRACT: “‘They have put a rope around my neck by bringing me here’: A Historical Exploration of Witchcraft Trials in the Transkeian Territories, 1882-1906” investigates neglected historiographical terrains by exploring the Transkei region, located in the Eastern Frontier of the Cape Colony, at the cusp of political transition when local African groups began to lose autonomy in the region. Witchcraft cases recorded in the arguably tainted colonial source, the Bantu Affairs Commission, serve as a lens from which to foreground the varying and complex philosophies, motivations and explanations of individual, and more specifically, group acts of witchcraft activities in the region. Probing these courtroom narratives exposes the internal juxtaposition of power and the forging of new alliances within and between African communities. Globally, the intricate relationship between witchcraft, power and conflict are made apparent within the existing literature. This dissertation argues that during this transitional period, witchcraft accusations brought before the courts were more reflective of communal factions and friction within small communities, as groups vied to maintain, and at times extend, their sphere of influence. These groups were intimately involved with colonial agents in negotiating the conditions of the fluctuating politico-legal system and, therefore, cannot be simply farmed as powerless victims during this transition. As such, witchcraft accusations were not only a manifestation of impending political conquest, economic change and environmental disasters, but allowed for the, albeit brief, renegotiation of African political power and politics in the aftermath of outright conflict and clandestine political treaties.