Inherited susceptibility to breast cancer.

Four genes are now known to be responsible for inherited susceptibility to breast cancer: the BRCA1 gene on chromosome 17q21, the ataxia-telangiectasia (AT) gene (11q22-q23), the TP53 gene (17p13.1) and the androgen receptor (AR) (Xq11.2-q12). These genes, however, differ dramatically in terms of the risk of breast cancer that they confer, the proportion of breast cancer incidence that they account for and the other cancers and other phenotypes with which they are associated. Genetic linkage studies have shown that some high risk breast cancer families, particularly those where breast cancer occurs in association with ovarian cancer, are due to a gene on chromosome 17q known as BRCA1. The BRCA1 gene is estimated to confer a breast cancer risk of about 70% by age 70, and may account for about 2% of overall breast cancer incidence, although a higher proportion of younger cases. Germline mutations in the TP53 gene are responsible for a high proportion of LI-Fraumeni families, in which breast cancer occurs in association with childhood sarcomas and other cancers. In such families, the risk of breast cancer is over 50% by age 50, and the risk of all cancers is nearly 100%; germline TP53 mutations are, however, probably responsible for much less than 1% of all breast cancer. By contrast, heterozygotes for the AT gene carry a much more moderate risk of breast cancer. This gene, however, is much more common in the population and may account for 7% or more of breast cancer incidence. Finally, germline mutations in the androgen receptor are known to cause male breast cancer, but this has only been demonstrated in two families. Evidence from linkage and population based studies suggests that these genes may account for about one half of the observed familial clustering of breast cancer; other breast cancer susceptibility genes therefore remain to be identified.