Breast cancer genes and the surgeon

Two genes, called BRCA-1 and BRCA-2, have been identified that appear to be responsible for the majority of familial breast cancer syndromes. These genes now play a prominent role in the practice of the surgeon treating breast cancer. Additional genes, PTEN (Cowden disease), MSH1 or MLH2 (HNPCC), and p53 (Li-Fraumeni syndrome) are responsible for other breast cancer syndromes but have not yet entered the clinical arena on a large scale. The risk of breast and ovarian cancer by age 70 in a BRCA-1 mutation carrier is estimated at 55-75% and 16-26 %, respectively, overall, and as high as 87% and 44% in those with a strong family history. The cancer risks associated with BRCA-2 mutations appear to be somewhat lower than those of BRCA-1. BRCA mutations show a strong founder effect. This is best recognized in the Ashkenazi Jewish community, in which the incidence of one of three characteristic mutations is about 2%. In other ethnic groups the pattern of mutations is different, with over 100 distinct mutations throughout the genes having been described. Most mutations so far have been frame-shift or mis-sense mutations, although large deletions have also been described. Thus, in most situations, assessment of the whole coding sequence is required to confirm or exclude a mutation. Guidelines to suggest who is likely to be a mutation carrier are being clarified, but the appropriate management of someone who tests positive remains difficult. Prophylactic mastectomy and oophorectomy are likely to offer substantial gains in life expectancy to mutation carriers, especially for young women with a strong family history. Unfortunately, there are no currently available strategies to eliminate the risk of breast or ovarian cancer. The psychological impact of testing also remains poorly understood, and the danger of various forms of discrimination remain. These factors must be clearly understood by all parties prior to testing. The process of a dynamic, interactive informed consent--much more than a simple printed document--and also counseling are central to the testing process.