Hereditary breast cancer (HBC), caused by mutations in tumour suppressor genes, has been well
studied in Caucasian and Ashkenazi Jewish populations. Little is known about the genetic aetiology
or the clinical epidemiology of HBC in African and South African black populations. Founder
mutations within specific genes have been described for numerous populations worldwide. In South
African black women, breast cancer often presents with early age of onset, rapid progression of
disease and adverse histological phenotypes. It is possible that mutations within already described
HBC-associated genes account for this phenotype in the South African black population. Genetic
mutations within the BRCA1 and BRCA2 genes contribute to the development of breast cancer in
high-risk cancer patients internationally. The proportion of breast cancers caused by mutations in
the BRCA1 and BRCA2 genes in the local black population is currently not well understood.
This study screened 33 South African black women presenting with early onset, high-risk breast
cancer, for genetic mutations in the BRCA1 and BRCA2 genes. These individuals were selected on
predefined high-risk criteria, including early age of disease onset, family history and cancer histology.
Mutation screening was done using bi-directional Sanger sequencing of the exons of both genes, and
MLPA analysis.
A total of 59 distinct single nucleotide variants were found in the BRCA1 and BRCA2 genes. Three of
these variants are pathogenic or likely pathogenic (BRCA1: c.431dupA; BRCA2: c.582G>A &
c.7712A>G). Five novel variants with unknown clinical significance were also found (BRCA1:
c.3751T>G, c.306A>C, c.5332+78C>T, c.212+66A>G; BRCA2: c.681+10T>G). There is little evidence to
suggest that these novel variants are likely to have a functional impact and to be pathogenic. The
remaining 51 variants were previously reported. No large gene/exon deletions or duplication
mutations were found on MLPA analysis.
The allele frequency data of the 51 previously reported variants were compared to the allele
frequencies of two separate control groups: an ethnically matched control group (established and
investigated in-house by a previous Masters student in the Division) and the 1000 genomes project
data. This comparison was done to screen for tag SNPs for future genetic association studies in black
South Africans and to evaluate potential background genetic differences within the BRCA genes of
different African populations. One allele within the BRCA1 gene occurred at a frequency which was
statistically significant as compared to the normal South African black population and one allele
within the BRCA2 gene was statistically significant. The two control groups were also compared
against each other. The allele frequencies were significantly different between the two control v
groups, suggesting that other African population groups (1000 genomes project data) do not serve
well as control groups for sub-Saharan African populations.
Genetic mutations within the BRCA1 and BRCA2 genes account for approximately 10% (3/33) of the
breast cancer cases within this high-risk cohort. Thus, the proportion of BRCA mutations contributing
to the development of inherited breast cancer in sub-Saharan blacks appears to be in keeping with
data reported for other ethnic groups. No evidence of any founder mutation/s was evident, although
the sample size tested here was too small to exclude their existence.