Breast cancer is the most common cancer in South African women. Approximately 5¬10% of all breast cancer cases are due to an inherited predisposition, resulting from mutations in tumour suppressor genes. The BRCA1 gene on chromosome 17q is one such tumour suppressor gene, that when mutated confers an increased risk of breast/ovarian cancer in carriers. To date, more than 500 different BRCA 1 mutations have been reported worldwide. Some of these mutations are frequently reported and others occur commonly in certain population groups. These population-specific differences in mutations represent founder effects, whereby a single ancestral mutation accounts for the majority of breast cancer cases. This study was undertaken as the nature and frequency of BRCA1 mutations in South African breast/ovarian cancer families is unknown. Fifty-one breast/ovarian cancer families were screened for three commonly occurring mutations (185deIAG, 4184del4 and 5382insC) using polymerase chain reaction (PCR) and allele-specific oligonucleotide (ASO) hybridisation. The protein truncation test (PTT) was utilised to detect truncating mutations in the large exon 11, and the remaining coding exons were screened for mutations using exon-by-exon PCR single strand conformation polymorphism/heteroduplex analysis (SSCP/HA). Seven disease-causing mutations were identified in 15 families, consisting of five different frameshift mutations and two different nonsense mutations. Four Ashkenazi Jewish families were found to harbour the 185delAG mutation; the 5382insC mutation was identified in two Afrikaner families and one Ashkenazi Jewish family. Haplotype analysis revealed that the four Ashkenazi families share the common Ashkenazi Jewish haplotype, suggesting a common ancestor for these families. Similarly, the two Afrikaner families share the same haplotype as families of north and east European ancestry with the 5382insC mutation. The haplotype of the Ashkenazi Jewish family with this mutation was however different to the linked haplotype, indicating a recombination event or an independent mutation. Both these mutations are thought to have occurred in or before the medieval period. Furthermore, four Afrikaner families were found to carry the novel E881X nonsense mutation, which has not been previously described. Haplotype analysis of these families suggested that these patients share a common ancestor, and genealogic studies have identified the founding couple for this mutation, who both arrived in the Cape from France in the late 1600s. Four additional families were found to harbour BRCA1 mutations by SSCP/HA. Three of these mutations have not been previously reported - the S451X nonsense mutation (identified in a family of Scottish origin), the 1493delC mutation identified in an Afrikaner family, and the 4957insC mutation identified in an Indian family. The 448insA mutation was identified in a family of German origin, where the patient had cancer of the fallopian tubes. A number of different described polymorphisms and variants of unknown functional significance were also identified. This is the first study to show that BRCA1 is involved in South African breast/ovarian cancer families, to the extent that 29.4% (15/51) of families have BRCA1 mutations. Furthermore, minor founder effects in the Afrikaner population have been demonstrated. These results enable improved genetic counselling and clinical management of mutation positive families as well as subsequent testing of family members.
Dissertation (MSc (Human Genetics))--University of Pretoria, 2005.