Estrogen receptor transcription and transactivation: Genetic modifiers of cancer risks conferred by BRCA1 and BRCA2

Both genetic and environmental factors are thought to interact with BRCA1 and BRCA2. The influence of nongenetic factors is demonstrated by the finding that even identical carrier twins may differ in disease history. Simple chance may determine age of onset, because multiple genetic mutations are required for full tumorigenesis. Thus far we are not even sure whether modifiers of BRCA-conferred risk actually exist, but some suggestive associations have been reported, which will require independent confirmation. Rare alleles at HRAS1 were found to increase risk of ovarian cancer in BRCA1 carriers, whereas breast cancer risk has been found to be modified by rare alleles at the androgen receptor. Among Ashkenazi Jewish women, a polymorphism in the 5' UTR of the RAD51 gene increased risk of breast cancer fourfold, but only in carriers of the BRCA2-6174delT.