Screening of young and/or familial African breast cancer patients for the presence of BRCA mutations
| dc.contributor.advisor | Van der Merwe, N. C. | |
| dc.contributor.advisor | Visser, B. | |
| dc.contributor.author | Peter, Namhla | |
| dc.date.accessioned | 2015-11-11T09:42:59Z | |
| dc.date.available | 2015-11-11T09:42:59Z | |
| dc.date.copyright | 2014-01 | |
| dc.date.issued | 2014-01 | |
| dc.date.submitted | 2014-01 | |
| dc.description.abstract | English: Screening for mutations within the BRCA1 and BRCA2 genes is a daunting task due to the length of the genes and the absence of mutational hotspots. An additional contributing factor is the genetic diversity within the Black ethnic groups of Africa, including the Sotho/Tswanas of the Free State. As no information was available regarding the prevalence of BRCA mutations within this group, this pilot study was launched in an attempt to determine the genetic component attributable to BRCA mutations in BC development. The selection criteria were not optimal and possible sporadic or single cases were included which according to literature, is not associated with mutations within the two familial BC genes. This resulted in a low percentage of disease-causing mutations being detected. It is proposed that the selection criteria in the future should emphasize the selection of bilateral BC cases with or without a positive family history. This characteristic seems to be more closely associated with familial BC in the Black patients than an early age at onset. The latter could be masking the familial BC cases, as the median age of onset of the disease in Black ethnic groups is 48. Two disease-causing mutations were identified, one within each of the genes. Both mutations were detected with PTT as they are located within exon 11. This indicates that this technique, although based on older technology, is still a valuable screening technique as it is cost-effective and less time consuming than screening the larger exons with for example high resolution melting (HRM). The two mutations are both situated within critical regions of the genes. BRCA1 c.2069_2072delAAAG,p.Lys653SerfsX699 is located within the binding domain of Rad50 whereas BRCA2 c.6455_6455delT,p.Lys2075ArgfsX2078 is located in BRC repeat 8. The presence of both these mutations will result in a truncated protein that would probably not be able to participate in DNA repair in response to DNA damage and cell cycle control (Green and Lin, 2012). This could result in chromosome instability and therefore tumour formation. Both mutations are novel and have not been detected internationally nor in the Black population residing in Gauteng SA. As all mutations detected thus far for the Black SA population seem to be limited to a single family and with no founder mutations found, full screening of both these genes remains the golden standard. Functional studies should be performed for the intronic variant BRCA2 c.517-4C>G (g.32900632C>G, rs81002804) detected in various patients. As this intronic variant is located only four bp from the start of exon 7, it could play a role in creating an alternative splice site. These studies together with the analysis of control individuals from the various Black SA ethnic groups will resolve the question whether this variant has the potential to be disease-causing. | en_ZA |
| dc.description.abstract | Afrikaans: Sifting vir mutasies in die oorerflike borskanker gene BRCA1 en BRCA2 is ‘n senutergende taak. Dit word bemoeilik deur die grootte van elkeen van hierdie gene sowel as die afwesigheid van spesifieke areas waarin foute algemeen voorkom. Die genetiese variasie teenwoordig in die swart bevolkingsgroepe, insluitend die Sotho/Tswana etniese groep van die Vrystaat, bemoeilik hierdie taak verder. Hierdie studie is ge-inisieer weens die gebrek aan inligting aangaande die teenwoordigheid van BRCA mutasies vir hierdie bevolkingsgroep. Die studie het dus gepoog om te bepaal tot watter mate BRCA mutasies bydra tot die genetiese komponent van oorerflike borskanker vir hierdie groep. Die seleksie kriteria tydens hierdie studie was nie optimaal nie. Die vermoede bestaan dat verskeie sporadiese borskanker gevalle ingesluit was, wat daartoe gelei het dat die persentasie positiewe resultate baie laag was. Volgens literatuur, is daar geen verband tussen sporadiese borskanker gevalle en mutasies in die oorerflike borskanker gene nie. Aangesien bilaterale borskanker in swart pasiënte wel ‘n assosiasie toon met die oorerflike tipe, word daar voorgestel dat toekomstige studies hierdie eienskap sal gebruik om sodoende meer potensiëel oorerflike gevalle in te sluit. Indien slegs ‘n vroëe ouderdom van diagnose gebruik word as insluitings kriterium, kan dit die persentasie oorerflike gevalle verskuil aangesien die gemiddelde ouderdom van borskanker diagnose 48 is vir die swart bevolkingsgroepe. Twee siekte-veroorsakende mutasies is gevind, een in BRCA1 en een in BRCA2. Hierdie mutasies is albei in ekson 11 van die onderskeie gene geleë en is geïdentifiseer deur van die verkorte proteïen toets (PTT) gebruik te maak. Die resultate het die waarde van PTT opnuut geïllustreer ten spyte daarvan dat dit eintlik ou tegnologie is. Die betrokke metode is baie meer koste effektief en tyd besparend om groot koderende areas te deursoek, wanneer dit byvoorbeeld met HRM vergelyk word. Die twee siekte-veroorsakende mutasies is in kritiese areas van beide hierdie gene geleë. BRCA1 c.2069_2072delAAAG,p.Lys653SerfsX699 lê binne die bindingsgebied van Rad50 met BRCA1, terwyl BRCA2 c.6455_6455delT,p.Lys2075ArgfsX2078 geleë is in BRC herhaling 8. Die teenwoordigheid van beide hierdie mutasies lei heel waarskynlik tot die vorming van verkorte polipeptiede wat nie die selsiklus kan beheer en gevolglike DNA skade kan herstel nie (Green and Lin, 2012). Dit kan weer lei tot onstabiele chromosome wat op hulle beurt aanleiding tot die vorming van gewasse kan gee. Nie een van die twee mutasies is al voorheen vir beide internasionale of die plaaslike swart bevolking beskryf nie. Die mutasies bekend is dus huidiglik beperk tot enkele families. Aangesien geen stigters- of herhalende mutasies tot dusver gevind is nie, bemoeilik dit diagnostiese toetsing. Die DNA van swart pasiënte moet dus tans volledig deurgesoek word met behulp van DNA volgordebepaling as die goue standard. Funksionele studies is egter nodig om te bepaal of die BRCA2 c.517-4C>G (g.32900632C>G, rs81002804) variant teenwoordig in intron 6 siekte- veroorsakend kan wees. Aangesien hierdie variant vier basisse vanaf die begin van ekson 7 lê, kan die verandering moontlik ‘n nuwe herkenningsgebied vir die uitsny van ekson 7 te weeg bring. Hierdie addisionele studies, sowel as die toets van normale kontrole individue vir die teenwoordigheid van die variant, sal meer lig op die moontlikheid werp. | af |
| dc.identifier.uri | http://hdl.handle.net/11660/1613 | |
| dc.language.iso | en | en_ZA |
| dc.publisher | University of the Free State | en_ZA |
| dc.rights.holder | University of the Free State | en_ZA |
| dc.subject | Dissertation (M.Med.Sc. (Human Genetics))--University of the Free State, 2014 | en_ZA |
| dc.subject | Breast -- Cancer -- Patients | en_ZA |
| dc.subject | Breast -- Cancer -- Genetic aspects | en_ZA |
| dc.subject | Nucleotide sequence | en_ZA |
| dc.subject | Africans -- Diseases | en_ZA |
| dc.subject | Familial breast cancer | en_ZA |
| dc.subject | Mutation screening | en_ZA |
| dc.subject | BRCA1 | en_ZA |
| dc.subject | BRCA2 | en_ZA |
| dc.subject | Sotho/Tswana population | en_ZA |
| dc.subject | SSCP, HA, PTT, DNA sequencing | en_ZA |
| dc.title | Screening of young and/or familial African breast cancer patients for the presence of BRCA mutations | en_ZA |
| dc.type | Dissertation | en_ZA |