Inherited predisposition and breast cancer: modifiers of BRCA1/2-associated breast cancer risk.

Germline mutations in the BRCA1 and BRCA2 (BRCA1/2) genes explain a substantial proportion of hereditary breast and ovarian cancer. Women who have inherited a mutation in one of these genes are at increased risk to develop breast and/or ovarian cancer, although there is variability in the manifestation of tumors by age and site. This variability may be explained, in part, by the BRCA1/2 mutation type or location. However, it is also possible that risk-modifying factors exist that explain interindividual variability in cancer risk. These factors include genes at other loci and endogenous or exogenous exposures. A more complete understanding of factors that modify cancer risk in BRCA1 and BRCA2 mutation carriers may help to refine estimates of cancer risk. A number of exposures, including reproductive history and exogenous hormone use, have been implicated as BRCA1/2-associated cancer risk modifiers. Similarly, genes involved in hormone metabolism, including the AIB1 and AR genes, have been linked with altered breast cancer risk. Therefore, although germline BRCA1/2 mutations raise a woman's breast and ovarian cancer risk, other factors may interact with BRCA1/2 mutations to modulate this risk.