Breast Cancer Susceptibility Genes: Current Challenges and Future Promises

Recent advances in understanding the basis for breast cancer that clusters in families represent a rare combination of spectacular scientific achievements and immediate clinical applications. In the past 5 years, we have moved from skepticism that single genes could be responsible for inherited forms of common adult cancer to the rapid organization of dozens of clinics designed to provide DNA-based susceptibility testing for mutations in several such recently isolated genes. These discoveries provide both critical tools for understanding the molecular events that precede the development of clinical breast cancer and the information necessary to identify women at exceptional risk for developing breast and ovarian cancer. However, they also highlight the profound lack of knowledge that still exists in all facets of breast cancer genetics. The unknowns range from how these genes function at the molecular and cellular levels to the psychosocial, ethical, and legal effects of susceptibility testing. What is clear is that these genetic discoveries are already affecting many patients and practitioners, few of whom are prepared to incorporate genetic testing and counseling into clinical practice.

Overall, inherited breast cancer is thought to account for about 5% to 10% of all cases of breast cancer. BRCA1 was the first major breast cancer susceptibility gene to be identified [1] and isolated [2]. Alterations in BRCA1 are thought to be responsible for approximately half of all inherited breast cancer, 70% of inherited breast cancer in women younger than 45 years of age at diagnosis, and almost all inherited breast-ovarian cancer [3]. Recent studies have begun to define the incidence of BRCA1 mutations outside of recognized breast cancer families, providing evidence that 5% to 10% of women younger than 40 years of age who have received a diagnosis of breast cancer may have BRCA1 alterations [4, 5]. Furthermore, a …