Summary of Breast Cancer Genetics Project Funded by CANSA at the University of the Witwatersrand

A CANSA-funded study analysed health records and genetic test results from 534 breast cancer patients who attended genetic counselling in the Western Cape and 115 of their relatives. About 18% of the breast cancer patients carried a harmful genetic variant linked to breast cancer, with similar rates across patients of African, Mixed and European ancestries. Although most patients accepted genetic testing, uptake among family members was much lower, limiting opportunities for prevention and early detection. Risk-reducing mastectomy was accepted by 52% of unaffected female family members who carried a harmful genetic variant.

The study also included genetic testing of 272 Black South African women diagnosed with breast cancer at or before the age of 50 years who were recruited through the population-based Johannesburg Cancer Study. The purpose was to assess the prevalence of harmful genetic variants in women of African ancestry from the general population with young-onset breast cancer. Harmful variants were identified in just over 10% of women in both age groups, those diagnosed at age 40 or younger and those diagnosed between the ages of 41 and 50. These findings highlight the potential value of expanding genetic testing beyond the current South African National Department of Health guidelines, which recommend testing for women diagnosed at age 40 or younger, to include women diagnosed at age 50 or younger.

The harmful genetic variants described above, which are individually rare, are located in a relatively small number of genes such as BRCA1 and BRCA2, which have long been associated with a high risk of breast cancer worldwide. More recent research has shown that hundreds of common genetic variants exist, each associated with a small (5-10%) increase in cancer risk. However, when an individual inherits a substantial number of these common variants, their lifetime risk of cancer can increase considerably.

These variants are identified through large-scale genetic studies that analyse millions of common variants across the human genome in thousands of cancer cases and healthy controls. Findings from such studies have been used to develop so-called polygenic risk scores that estimate the lifetime risk of developing a particular cancer. However, almost all of this research has been conducted in populations of European or Asian ancestry.

Researchers recently published a genome-wide study involving 3,500 South African women of African ancestry and identified common genetic variants near genes not previously associated with breast cancer. The study also demonstrated that polygenic risk scores developed in European populations had limited value in distinguishing South African breast cancer patients from unaffected women. Building on these findings, researchers are now conducting a much larger study in South African women as part of a global breast cancer genetics initiative aimed at identifying additional risk genes and developing polygenic risk scores that are more relevant to African populations.

The overall goal of this research is to identify genetic tests that are relevant to local populations and to discover genes that may contribute to the development of more targeted and effective therapies for this increasingly common cancer.