Inheritance of a germ line mutation in the BRCA1 or BRCA2 (BRCA1/2) gene confers early onset breast and ovarian cancer risk that is many times higher than that in the general population. Gao and colleagues report that a polymorphism in tumor suppressor gene RASSF1A (A133S) also confers an increased risk of developing breast cancer in Caucasian women. Importantly, they found that the average age at breast cancer diagnosis for BRCA1/2 mutation carriers with A133S is six years earlier than in individuals with wild-type RASSF1A. They hypothesized that RASSF1A modifies the risk of breast cancer in BRCA1/2 mutation carriers.
This finding provides more evidence of the importance of the RASSF1A tumor suppressor gene as the A133S variant has been shown to have lost functional activity compared to wild-type RASSF1A. It also suggests the need for a large-scale study to validate the effect of A133S in the development of breast and other types of cancer. If confirmed, RASSF1A A133S could be developed as a molecular biomarker for refining cancer risk estimates for women at higher risk for breast cancer. Women with a BRCA1/2 mutation and wild-type RASSF1A (A133S) might use such information to aid decisions regarding timing of risk-reducing interventions, such as prophylactic surgery or chemoprevention. For details, see the article by Gao and colleagues on page 22 of this issue.