The effect of selected polymorphisms in the p53 pathway as potential genetic modifiers of cancer risk and penetrance in female Afrikaner BRCA2 carriers

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dc.contributor.advisorVan der Merwe, N. C.
dc.contributor.advisorVisser, B.
dc.contributor.authorDajee, Bhavini Kiran
dc.date.accessioned2015-08-03T08:12:37Z
dc.date.available2015-08-03T08:12:37Z
dc.date.issued2007-11
dc.description.abstractGermline 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 5’ 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 5’ 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.en_ZA
dc.identifier.urihttp://hdl.handle.net/11660/777
dc.language.isoenen_ZA
dc.publisherUniversity of the Free Stateen_ZA
dc.rights.holderUniversity of the Free Stateen_ZA
dc.subjectBreast -- Cancer -- Genetic aspectsen_ZA
dc.subjectGenetic polymorphismsen_ZA
dc.subjectRecombinant haplotypeen_ZA
dc.subjectPenetranceen_ZA
dc.subjectEpidemiological characteristicsen_ZA
dc.subjectMDM2en_ZA
dc.subjectWAF1en_ZA
dc.subjectTp53en_ZA
dc.subjectModifiersen_ZA
dc.subjectSNPsen_ZA
dc.subjectPhenotypic expressionen_ZA
dc.subjectFamilial breast canceren_ZA
dc.subjectDissertation (M.Med.Sc. (Human Genetics))--University of the Free State, 2007en_ZA
dc.titleThe effect of selected polymorphisms in the p53 pathway as potential genetic modifiers of cancer risk and penetrance in female Afrikaner BRCA2 carriersen_ZA
dc.typeDissertationen_ZA
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