Breast Cancer Susceptibility and the DNA Damage Response

Breast cancer is a disease caused by a complex combination of genetic and environmental factors. It is one of the most common types of cancer affecting women in the Western world. In 2004 in the United States, it is estimated that more than 200,000 new cases of breast cancer will be diagnosed and over 40,000 will die of this disease. Linkage analysis of families with a high risk of breast cancer has identified two major susceptibility genes: BRCA1 and BRCA2.1,2 In the context of large, multiple-case families, the BRCA1 and BRCA2 genes are numerically the most important, accounting for more than 80% of families with six or more cases of both early-onset breast cancer and ovarian cancer.3 However, the probability of harboring a mutation is much lower in families with fewer cases of the disease, and population studies have demonstrated that these genes account for only a minority of the overall familial risk of breast cancer. In fact, as many as 60% of families with site-specific female breast cancer cannot be explained by mutations in BRCA1 and BRCA2.4,5 In addition,mutations in these genes are relatively rare in the general population. Together they account for less than 10% of all breast cancer cases4,6 (Fig 1). Therefore, the challenge is how to identify individuals at risk for the remaining cases. Conceivably, if we could identify the major genetic factors that contribute to breast cancer risk, we would be able to not only provide comprehensive early identification of individuals at risk but also tailor prevention and treatment regimens to adequately address specific molecular changes in these cancers.