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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-07042014-131023 |
| Date | 04 July 2014 |
| Creators | Peter, Namhla |
| Contributors | Dr B Visser, Dr NC van der Merwe |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-07042014-131023/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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