Germline mutations in BRCA2 confer a high risk for the development of breast
cancer in the Afrikaner population. A great deal of variability in the development of
the disease has been observed among mutation positive family members.
Evidence suggested that genes affecting breast cancer risk in the general
population could potentially also affect breast cancer risk in BRCA mutation
carriers. The cell cycle control pathway was selected as a candidate as the
functional loss of the tumour suppressor protein p53 is a common feature in diverse
human cancers. The ability of this protein to sense cellular damage and halt the
progression of the cell cycle or direct the cells to apoptosis is essential in
preventing tumourigenesis.
The aim of the study was an attempt to identify potential genetic modifiers of breast
cancer risk and penetrance in Afrikaner women carrying the South African founder
BRCA2 c.8162delG mutation. It involved environmental factors as well as six
polymorphisms detected in critical genes of the Tp53 pathway. The investigated
polymorphisms included three variants previously detected in Tp53 (intron 3, exon
4 and intron 6), a polymorphism present in the promoter of MDM2 and two SNPs
identified in WAF1 (intron 2 and exon 2).
The epidemiological study failed to identify any specific characteristic associated
with an increased or protective breast cancer risk and did not explain the observed
residual variation. Of the six polymorphisms studied, only one proved to be
statistically significant, namely the 5â splice-site variant in intron 2 of WAF1. This
polymorphism seemed to explain the variation in penetrance for some of the
families, but needs to be confirmed by more extensive studies. A breast cancer
recombinant haplotype was compiled using the most informative variants, namely
the polymorphism in the MDM2 promoter, the 5â splice-site variant in intron 2 of
WAF1 and the SNP in exon 4 of Tp53, but proved to be uninformative. Association
studies including gene to gene and gene to environment interactions could assist
researchers in their understanding of the mechanistic basis of the polygenic nature
of breast cancer.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-02152010-141652 |
| Date | 15 February 2010 |
| Creators | Dajee, Bhavini Kiran |
| 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-02152010-141652/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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