Breast/ovarian cancer susceptibility in SA women Role of DNA homologous recombination genes – Prof Elizabeth Jv Rensburg
Prof Elizabeth Jansen van Rensburg
Breast/ovarian cancer susceptibility in South African women: Role of DNA homologous recombination genes.
Cancer of the breast is the most common cancer in South African women. The most important risk factor for developing cancer of the breast is a family history of the disease. Two high penetrance breast cancer susceptibility genes, BRCA1 and BRCA2 are clinically the most important genes associated with hereditary breast cancer.
Previously we have shown that 67% of high-risk SA breast cancer families (multiple affected women) carry a BRCA1 or BRCA2 germ-line mutation. We have also found that 6,4% of a hospital based cohort of Black women, diagnosed with breast cancer aged younger than 55 years, carried a BRCA1/BRCA2 mutation.
These genes are important in maintaining the genomic stability of cells and have been shown to be linked to the DNA homologous recombination repair pathway. An interaction partner of the BRCA2 protein, PALB2, that promotes the localisation and stability of the BRCA2 protein in key nuclear structures allowing it to function in DNA repair, was also shown to be involved in breast cancer suppression. We found that pathogenic PALB2 mutations account for approximately 2% of SA early-onset breast cancer cases not selected for family history.
Recently we have shown that another gene, RAD51C, that is involved in recombination repair of DNA double-strand breaks, accounts for 1,4% of high-risk SA breast cancer families. All of these persons have been counceled with regard to their risks, and predictive testing of other at-risk family members are ongoing.
The involvement of the homologous recombination DNA repair genes BRCA1, BRCA2, PALB2 and RAD51C in breast cancer risk emphasises the importance of this mechanism in the etiology of breast cancer. Interestingly, a series of new therapeutic agents that are potent inhibitors of the poly (ADP-ribose) polymerase (PARP) family of enzymes have demonstrated important clinical activity in patients with breast or ovarian cancers that are caused by mutations in either the BRCA1 or 2 genes. As a whole, these agents have generated considerable attention because of their potential clinical activity for patients whose tumors harbor defects in the HR pathway.
Recent literature reported two new brease cancer susceptibility genes, RAD51D and XRCC2, that are also involvend in homologous recombination (HR) DNA repair. It would now be useful to determine whether XRCC2 and RAD51D are involved in the etiology of breast cancer in SA. Identification of varants within these genes will lead to the development of additional screening techniques to identify high-risk individuals who, just like the BRCA/PALB2/RAD51C mutuation positive women, can be offered counseling and help with the management of their risks. In addition it is important to identify women whose breast cancer is associated with the HR-DNA-repair dysfunction because they could benefit from specific treatments such as PARP inhibitors.
We propose to determine what proportion of the overall burden of breast cancer in SA women is attributable to mutations of the XRCC2 and RAD51D genes. A series of interrelated questions will be addressd, i.e. How do these frequencies differ by age at diagnosis, ethnic group or family history? Do tumours arising in XRCC2 or RAD51D mutation carriers differ from tumours arising in BRCA1/BRCA2 mutation carriers with regard to bioloical features as well as clinical behaviour? This data will allow us to assess the potential clinical and public health significance of XRCC2 and RAD51D mutations is SA women with breast cancer.