Thesis (MSc (Genetics))--University of Stellenbosch, 2005. / Breast cancer is a major cause of morbidity and mortality as it is the most common invasive cancer in women worldwide. The lifetime risk for South African women to develop breast cancer is one in 31. A family history of the disease is a well-established risk factor and germline mutations in the BRCA1 (breast cancer one) and BRCA2 (breast cancer two) tumour suppressor genes markedly increase the risk of developing breast cancer. A few hundred mutations spanning the entire coding sequences of both genes have already been reported. Numerous other breast cancer susceptibility loci have been identified, but results from association studies are discrepant. The checkpoint kinase gene, CHEK2, and specifically the CHEK2*1100delC variant has, however, consistently been implicated as a candidate low-penetrance breast cancer allele. To date, few comprehensive molecular-genetic studies have been completed for the various South African breast cancer populations. The aim of this study was to determine the BRCA1 and BRCA2 mutation spectrum and prevalence in two South African populations, namely Mixed Ancestry and Caucasian. The frequency of the CHEK2*1100delC mutation was also investigated. The patient group comprised 101 unrelated patients (98 women and 3 men), presenting with invasive breast cancer. Patients with a moderate family history of breast cancer (n=48) were screened for the CHEK2*1100delC allele and the coding sequences of the BRCA1 (partly completed in a previous study) and BRCA2 genes. Patients without a family history of the disease (n=53) were only screened for the CHEK2*1100delC allele. Mutation detection was done using combined single-strand conformation polymorphism and heteroduplex analysis (SSCP/HA), followed by DNA sequencing of the identified variants. Due to its size (~5kb), exon 11 of BRCA2 was sequenced directly after amplification, in seven overlapping fragments. Three deleterious BRCA1 mutations, 1623_1627delTTAAA, E881X and 5313delC have previously been identified in three patients from the study population. No additional pathogenic mutations have been detected in this gene during this study. Two deleterious BRCA2 mutations, 6677_6678insTA and 8162delG, were identified in two and three patients respectively. Overall, BRCA1 and BRCA2 mutations have been identified in 17% of the Mixed Ancestry patients and in 15.8% of the Caucasian patients. Together BRCA1 and BRCA2 mutations account for 16.7% of breast cancer in the study population. In addition, a number of silent polymorphisms as well as variants of unknown functional significance, both known and novel, were identified. The E881X variant, which has been reported as an Afrikaner founder mutation (Reeves et al. 2004), was identified in one patient of Mixed Ancestry, but none of the published European founder mutations have been detected in our patient group. This suggests a unique mutation spectrum for South African breast cancer patients. The prevalence of the BRCA2 mutations, 8162delG and 6677_6678insTA, has to be elucidated within a larger study group. Haplotype analysis will reveal whether these patients have a common ancestor. Our findings do not suggest the presence of the CHEK2 variant in South African breast cancer patients, but a larger study population has to be analysed to confirm this. The results of this study are in agreement with those from other populations, indicating that less than 20% of breast cancers that occur in individuals with a moderate-risk for developing breast cancer are due to BRCA1 and BRCA2 mutations. By determining the contribution of BRCA1 and BRCA2 mutations to breast cancer in this group of patients, one can assess the appropriateness of predictive or diagnostic DNA testing in the clinical setting.

Thesis (MSc)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: With knowledge of the human genome increasing constantly we are continually faced with new and potentially groundbreaking methods for managing, treating and/or identifying diseases and predisposition to diseases and conditions at a genetic level. The human cytochrome P450 (CYP) super-family of genes code for enzymes that can participate in metabolism of drugs and foreign chemicals and in steroid synthesis and metabolism. Mutations in these genes may contribute to clinically relevant diseases. In this study, the effects of mutations within four CYP genes were evaluated in two South African disease groups - variegate porphyria and breast cancer. Variegate porphyria (VP) has an unusually high incidence in South Africa due to the R59W founder mutation in the protoporphyrinogen oxidase (PPOX) gene that causes a disruption in the haem biosynthetic pathway. VP presents with variable clinical symptoms and has a relatively low penetrance. It is expected that environmental factors and modifier genes play a role in the clinical expression of VP. CYP genes are implicated as candidate modifier genes for the expression of VP due to the function they have in metabolising many drugs contraindicated in porphyria patients, and the necessity of haem binding to the apoprotein to produce a functional CYP enzyme. This is the first study to investigate CYPs as possible modifier genes for VP clinical expression. Six CYP polymorphisms (CYPIAlml, CYPIAlm2, CYPIA2 - 734 C>A, CYPIBI 8372 A>C, CYP2D6*3, CYP2D6*4), associated with four CYP loci, were genotyped in a VP population and a suitable control population. The results observed are suggestive of CYPIAlml and CYPIBI playing a role as modifiers for the clinical expression of VP as they were significantly associated (P<O.05) with the presence ofVP related symptoms. Breast cancer is one of the leading causes of death in women due to cancer. It is believed that breast cancer may be the result of co-participation between common DNA alterations and environmental exposures. Polymorphisms in enzymes involved with the metabolism of environmental exposures, such as the cytochrome P450 enzymes, are therefore expected to play an aetiological role in breast cancer. Two groups of South African breast cancer patients (Caucasian and of mixed ancestry) and population-matched controls were genotyped for four CYP polymorphisms (CYPIAlml, CYPIAlm2, CYPIA2 -734 C>A and CYPIBI 8372 A>C). This represents the first investigation of the potential role of CYPs as breast cancer risk modifiers in the two South African populations. Significant differences were observed (P<O.003) in genotype and allele frequencies between the breast cancer patients and controls for the CYPIBI 8372 A>C polymorphism in the population of mixed ancestry. Vast differences in allele frequencies were also observed between the two groups of breast cancer populations. These results emphasize the importance of population-based risk assessment when genetic testing and counselling for complex disease susceptibility is offered. The results of this study provide the first evidence suggesting a role for CYPs in modifying the clinical expression of VP and in acting as risk factors for developing breast cancer in a South African population. / AFRIKAANSE OPSOMMING: Met die konstante toename van kennis oor die mensgenoom kom ons voortdurend te staan voor nuwe metodes vir die beheer, behandeling en/of identifikasie van siektes en vatbaarheid vir siektes op 'n genetiese vlak. Die mens sitochroom P450 geensuperfamilie kodeer vir ensieme betrokke in die metabolisme van medisyne en ander chemiese stowwe en steroïed-sintese en -metabolisme. Mutasies in hierdie gene kan 'n bydrae lewer tot kliniese relevante siektes. In hierdie studie is die effek van mutasies in vier sitochroom gene bestudeer in twee Suid-Afrikaanse siekte groepe, variegate porfirie en borskanker. Variegate porfirie (VP) het 'n besonderse hoë frekwensie in Suid-Afrika as gevolg van die R59W stigter-mutasie in die protoporfirinogeen oksidase (PPOX) geen. Hierdie mutasie lei tot 'n versteuring in die heem biosintese padweg. VP presenteer met variërende kliniese simptome en het 'n betreklike lae penetrasie. Daar word vermoed dat omgewingsfaktore en kandidaat modifiserende gene 'n rol speel in die kliniese beeld van VP. Sitochroom P450 gene is geïdentifiseer as kandidaat modifiserende gene as gevolg van hulle rol in die metabolisme van verbode medikasie vir porfirie pasiënte, asook die binding van heem aan die apoproteïen wat noodsaaklik is vir die produksie van funksionele sitochroom P450 ensiem. Hierdie is die eerste studie wat sitochroom P450 gene as moontlike modifiserende gene vir die kliniese uitdrukking van VP ondersoek. Ses sitochroom P450 polimorfismes (CYPIAlml, CYPIAlm2, CYPIA2 -734 C>A, CYPIBI 8372 A>C, CYP2D6*3, CYP2D6*4) is ondersoek in beide 'n VP populasie en 'n geskikte kontrole populasie. Die resultate suggereer 'n rol vir CYPIAlml en CYPIBI in die modifisering van die kliniese uitdrukking van VP aangesien hulle betekenisvolle assosiasie (P<O.05) met die voorkoms van VP-verwante simptome getoon het. Borskanker IS een van die vernaamste oorsake van kankersterftes onder vroue. Borskanker IS waarskynlik die resultaat van interaksie tussen algemene DNSveranderinge en omgewings-blootstelling. Daar word dus verwag dat polimorfismes in ensieme betrokke by die metabolisme van omgewingselemente, soos byvoorbeeld die sitochroom P450 ensieme, 'n etiolgiese rol in borskanker sal speel. Die genotipes van twee groepe Suid-Afrikaanse borskanker lyers (Kaukasiërs en van gemengde herkoms) en populasie-passende kontroles is bepaal vir vier sitochroom P450 polimorfismes (CYPIAlml, CYPIAlm2, CYPIA2 -734 C>A, CYPIBI 8372 A>C). Hierdie studie verteenwordig die eerste ondersoek na die potensiële rol van sitochroom P450s as risiko-modifiserende faktore vir borskanker in die twee populasies. Betekenisvolle verskille (P<O.003) in genotipe en allele frekwensies is waargeneem tussen die borskanker lyers en kontroles vir die CYPIBI 8372 A>C polimorfisme in die gemengde herkoms populasie. Beduidende verskille in alleel frekwensies is ook waargeneem tussen die twee borskanker populasies. Hierdie resultate beklemtoon die belangrikheid van populasie gebaseerde risiko-beraming wanneer genetiese toetse en voorligting vir komplekse siekte-vatbaarheid aangebied word. Die resultate van hierdie studie bied die eerste getuienis dat sitochroom P450s 'n rol kan speel in die modifisering van die kliniese beeld van VP en ook kan optree as as risiko faktore vir die ontwikkeling van borskanker in 'n Suid-Afrikaanse populasie.

Please read the abstract in the section 00front of this document / Thesis (DPhil)--University of Pretoria, 2010. / Medical Oncology / unrestricted

Treatment outcomes of young patients with invasive breast cancer treated radically at Groote Schuur Hospital from 2013 to 2017: A single centre study Background: Breast cancer is the leading cause of cancer- related deaths globally, and the commonest cancer in women under 40 years. There is currently a lack of data relating to treatment outcomes of young women with breast cancer particularly in low-and middle-income countries. Aim: This study aims to evaluate the treatment outcomes of young patients (under 40 years) treated radically for invasive breast cancer in a low-and middle-income setting. Settings: Groote Schuur Hospital, Cape Town, South Africa Methods: A retrospective review of 101 women under 40 years, with invasive breast cancer treated radically, between 2013 and 2017 was conducted. Patient characteristics, tumour characteristics, disease stage, treatment, and follow-up were recorded. Primary objectives included evaluating overall and disease free survival, and analysing recurrence patterns and clinicopathological features. Results: The five-year overall and disease free survival for the entire cohort was 77% and 51%, respectively. Five-year overall survival by molecular subtype showed that Luminal A had the best survival, while triple negative breast cancer had the worst overall survival. Conclusion: Young women with breast cancer have poor survival outcomes despite early presentation. There is limited data regarding breast cancer treatment outcomes in patients under forty years.

According to the 1 991 Annual Report of the Department of Health and Social Services of former Bophuthatswana, there were 364 reported malignant conditions found in women with cancer of the breast and cervix being the most prevalent. What causes great concern is t.he fact that patients present for the first time at health facilities during advanced stages of these diseases thus making the prognosis poor. Black patients in this study were found to present with cancer of the breast at an earlier age than their white counterparts. In addition to the above named problems, no facility exists for the treatment of cancer in the area of study and patients have to be referred to other areas. It was on the strength of the above observations that the researcher embarked upon this study to establish the effects of the diagnosis cancer and mastectomy on the victims. The aims of the study therefore were: to explore and describe the psycho-social effects of the diagnosis and treatment on Black women; develop guidelines for oncology nurses and doctors to assist with the adaptation of these patients to the diagnosis and treatment; and provide information that could lead to better training of oncology personnel as well as develop a proper support system to facilitate adjustment of the mastectomised patient to the disease and its treatment. Data were collected using the qualitative and quantitative approaches with individual in-depth interviews forming the main strategy. The findings revealed that the diagnosis cancer of the breast was equated with death among all respondents. The mastectomy added more stress for the patient, which was further compounded by chemo- and radiotherapy. The latter was described as causing more pain than the tumour itself. Problems experienced by the patients were reported to include: financial difficulties; general weakness; fear of recurrence and metastasis; concern for dependent children and fear of unemployment. All respondents in this study expressed the need for the formation of a voluntary care group, which could assist them with adaptation to the disease and its treatment. / Advanced Nursing Sciences / D. Lit. et Phil. (Advanced Nursing Sciences)

According to the 1 991 Annual Report of the Department of Health and Social Services of former Bophuthatswana, there were 364 reported malignant conditions found in women with cancer of the breast and cervix being the most prevalent. What causes great concern is t.he fact that patients present for the first time at health facilities during advanced stages of these diseases thus making the prognosis poor. Black patients in this study were found to present with cancer of the breast at an earlier age than their white counterparts. In addition to the above named problems, no facility exists for the treatment of cancer in the area of study and patients have to be referred to other areas. It was on the strength of the above observations that the researcher embarked upon this study to establish the effects of the diagnosis cancer and mastectomy on the victims. The aims of the study therefore were: to explore and describe the psycho-social effects of the diagnosis and treatment on Black women; develop guidelines for oncology nurses and doctors to assist with the adaptation of these patients to the diagnosis and treatment; and provide information that could lead to better training of oncology personnel as well as develop a proper support system to facilitate adjustment of the mastectomised patient to the disease and its treatment. Data were collected using the qualitative and quantitative approaches with individual in-depth interviews forming the main strategy. The findings revealed that the diagnosis cancer of the breast was equated with death among all respondents. The mastectomy added more stress for the patient, which was further compounded by chemo- and radiotherapy. The latter was described as causing more pain than the tumour itself. Problems experienced by the patients were reported to include: financial difficulties; general weakness; fear of recurrence and metastasis; concern for dependent children and fear of unemployment. All respondents in this study expressed the need for the formation of a voluntary care group, which could assist them with adaptation to the disease and its treatment. / Advanced Nursing Sciences / D. Lit. et Phil. (Advanced Nursing Sciences)

A qualitative research design and an ethno-nursing research method were used to identify cultural factors influencing Xhosa women's health seeking behaviours associated with breast lumps. Focus group interviews were conducted to obtain data. The research results revealed that these Xhosa women with breast lumps did not disclose some cultural factors which influenced their health seeking behaviours associated breast lumps. Registered nurses, sharing the same culture and language as the Xhosa women, revealed that Xhosa women with breast lumps sought treatment from traditional healers, prior to seeking medical care from the hospital and/or clinics. When they arrive at the hospital/clinics the breast lumps have often progressed to advanced ulcerated breast cancer, with poor prognoses and poor treatment outcomes. Xhosa women lacked knowledge about the management of breast lumps. Health promotion efforts should address this issue at Primary Health Care services in the Eastern Cape. / Health Studies / M.A. (Health Studies)

A qualitative research design and an ethno-nursing research method were used to identify cultural factors influencing Xhosa women's health seeking behaviours associated with breast lumps. Focus group interviews were conducted to obtain data. The research results revealed that these Xhosa women with breast lumps did not disclose some cultural factors which influenced their health seeking behaviours associated breast lumps. Registered nurses, sharing the same culture and language as the Xhosa women, revealed that Xhosa women with breast lumps sought treatment from traditional healers, prior to seeking medical care from the hospital and/or clinics. When they arrive at the hospital/clinics the breast lumps have often progressed to advanced ulcerated breast cancer, with poor prognoses and poor treatment outcomes. Xhosa women lacked knowledge about the management of breast lumps. Health promotion efforts should address this issue at Primary Health Care services in the Eastern Cape. / Health Studies / M.A. (Health Studies)