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Breast/Ovarian Cancer Susceptibility in SA Women: Clinical Utility of Multi-gene Panel Testing

Prof Lizette Jansen van Rensburg

Project ended 30 June 2020

Prof Lizette Jansen van Rensburg

Title of the project

Breast/ovarian cancer susceptibility in South African women: Clinical utility of multi-gene panel testing.

Project Description

Worldwide breast cancer is the most common cancer in women. In South Africa, breast cancer ranks first in White, Coloured, and Asian women and second in Black women. Cancer development is a multistage process, which results from a process of genetic changes, some inherited, some induced by environmental exposures, and some occurring by chance. Much progress was made in recent years in the identification of genetic changes that predispose individuals to cancer. It is estimated that ~ 20% of female breast cancers are due to the inheritance of a mistake (mutation) in either of two genes called BRCA1 and BRCA2. Women who have inherited such mistakes are at a high risk of developing breast and/or ovarian cancer. These genes are important in maintaining the genetic stability of cells and are linked to a specific DNA repair pathway known as, DNA homologous recombination repair (HR). Recently, inherited mutations in other genes (> 18 genes) that function in DNA repair pathways were identified that are associated with hereditary breast /ovarian cancer. It is important to identify women who carry mutations in these genes because the presence of such mistakes could affect treatment, follow-up, and further cancer prevention in patients with breast or ovarian cancer and their relatives.

Genetic testing for cancer predisposition genes is an important advance in cancer medicine. With the advent of next-generation sequencing, simultaneous sequencing of multiple cancer susceptibility genes is available through multiplex panels at a cost comparable to that for single-gene testing. As we have been investigating breast cancer susceptibility in South Africans (with the support of CANSA grants) for some time now and have gathered a substantial volume of data/information, we are of the opinion that it is now an opportune time to embark on a translational study.

This study will determine how often multi-gene panel-based mutation screening (using targeted next-generation sequencing of cancer predisposition genes) will identify clinically actionable mutations among patients with breast cancer (unselected for family history of breast cancer). This is in order to investigate the feasibility of translating this type of testing to clinical practice. Specifically to provide breast cancer units (Surgeons, Oncologists, etc) with an enhanced ability to make informed decisions about patient care.

Non-scientific report

In this study, South African women with breast cancer, not specifically selected for age at diagnosis or an enriched family history of cancer, were screened for mistakes (mutations) in 94 cancer predisposition genes. These included 18 genes known to predispose to breast and/or ovarian cancer. We wanted to determine how often this type of testing would identify clinically actionable mutations in the patients, i.e. to what extent would these results enhance the ability of breast cancer units (Surgeons, Oncologists, etc) to make informed decisions about patient care?

We found that 14.3% (26/182) of black women with breast cancer carried a disease-causing mutation in one of five breast cancer susceptibility genes. Only 18% of these women reported a family history of cancer. Thus if family history was used as the criteria for testing of breast cancer susceptibility genes, 82% of the women who actually carried a disease-causing mutation in one of these genes, would not have been detected. BRCA1/BRCA2 disease-causing variants were found in 21 (80.8%) of these patients, and five patients (19.2%) carried mistakes in the non-BRCA breast-ovarian cancer predisposition genes. Of importance is that recurrent mutations account for 54% of the BRCA1 mutation-positive women of African ancestry. For women of European ancestry with breast cancer, unselected for family history of cancer, we found that ~ 15% carried a BRCA-disease-causing mutation. Two BRCA founder mutations unique to South Africa, account for 75% of the women with a BRCA1/2 mutation.

It is clear from the results that screening all of the 18 breast cancer predisposition genes in South Africans as a first step is not indicated. However, screening the two BRCA-genes in South African women diagnosed with breast cancer younger than 55 years, regardless of family history, would be of benefit.

The implications for the women who carry deleterious mutations are on two levels, firstly it may influence the choice of chemotherapeutic drugs for their treatment and secondly, their risk of developing second cancer has increased. Furthermore, their first-degree relatives may be offered testing (after appropriate counselling) to determine who are unaffected carriers of these mutations, as they can benefit from increased surveillance and cancer preventative strategies.

How this project was of value in the struggle against cancer

Applying the knowledge gained from this on-going study of breast cancer susceptibility genes, preventative/ early detection strategies may be developed that will reduce the incidence and mortality of breast cancer, benefiting South African women and society as a whole. Furthermore, it is important to identify women whose breast cancer is associated with Homologous Recombination-DNA-repair dysfunction because they could benefit from treatments that include PARP inhibitors.

This particular project has shown that screening the two BRCA-genes in S.A. women diagnosed with breast cancer younger than 55 years, regardless of family history, would be of benefit. The fact that founder/recurrent mutations represent a large proportion of the detected BRCA1 / BRCA2 mutations is significant. A test for these mutations could be implemented as a cost-effective screening step in a point of care (POC) test kit that can be performed on-site.

Future plans for this research project

We would like to develop a kit for the recurrent BRCA pathogenic variants in collaboration with Prof Maritha Kotze (Stellenbosch University) for use in the ParaDNA device. This would allow for on-site testing without having to transfer samples to a laboratory for analysis.


  1. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer (2019)
  2. BRCA1 and BRCA2 pathogenic sequence variants in women of African origin or ancestry (2019)
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