A single minor mutation in one gene has been the first factor identified as greatly increasing the risk of developing breast cancer at a comparatively young age among women who carry the BRCA2 gene mutation (Proceedings of the National Academy of Sciences 2001;98:3232-6).
The discovery was made by Dr Ephrat Levy-Lahad, a medical genetics researcher at Shaare Zedek Medical Center in Jerusalem, and her colleagues. Dr Levy-Lahad and her team looked at why only some women who carry the BRCA1 and BRCA2 mutations get breast cancer. They studied 257 carriers of these mutations at the Shaare Zedek Medical Center and at the Rambam Medical Center in Haifa.
One in 40 Jewish women of Ashkenazi (European) origin carries either the BRCA1 or BRCA2 mutation. Their risk of breast cancer is not higher than that in other populations, explained Dr Levy-Lahad, “but they are an excellent group to study because of their genetic homogeneity. Thus there are fewer variations, and results provide a clearer picture.”
The two mutations are responsible for about 10% of cases of breast cancer and 30% of cases of ovarian cancer. Dr Levy-Lahad discovered that a polymorphism on a different gene and chromosome, called RAD51, greatly influences the risk of contracting breast cancer among women who carry BRCA2.
It is known that BRCA1 and BRCA2 both work as part of a complex of proteins that repair damage to DNA and that this complex also includes the RAD51 protein. The RAD51 gene appears in two forms: a common one called 135G and a rare one called 135C; the rare form is found among 8% of women of Ashkenazi origin.
The team found that BRCA2 carriers who also have the rare RAD51 mutation are four times more likely to get breast cancer than those with the common mutation. All women with BRCA2 and the 135C mutation who were studied contracted breast cancer before the age of 58; half of those with the common form were completely healthy when they reached that age. Dr Levy-Lahad explained that the BRCA1 mutation is a more “powerful” cause of breast cancer than BRCA2, which needs “help” from other mutations to trigger it.
Women with a family history of these tumours can take a blood test to determine whether they carry a mutation that puts them at risk; carriers may be given tamoxifen as a preventive measure, are advised to have frequent check ups, and may even undergo prophylactic mastectomy or oophorectomy.
But advising carriers is complicated because some of them will not develop cancer. Until now, scientists have agreed that there are other factors, both hereditary and environmental, that cause variation in risk among carriers, but no one had identified any.