Low penetrance genes associated with increased risk for breast cancer

Much effort in recent years has been focused on understanding the factors t hat contribute to breast cancer risk. Two major susceptibility alleles, BRC A1 and BRCA2, have been identified, and the prevalence and penetrance of mu tations in these genes have been studied extensively. However, this work hi ghlights the fact that only a small proportion of breast cancer is due to m utations in the genes. Evidence for additional high penetrance genes exists , but it is becoming clear that an understanding of multiple lower penetran ce alleles will be necessary to fully define breast cancer risk. Work in th is area has focused on the analysis of polymorphisms of potential functiona l significance in several classes of genes, including those involved in car cinogen metabolism, oestrogen metabolite biosynthesis, steroid hormone rece ptor activation and DNA damage response. These studies are reviewed and a s trategy to use modification of breast cancer penetrance in families with kn own mutations in BRCA1 as a means of identifying additional low penetrance, or modifier, genes is discussed. (C) 2000 Elsevier Science Ltd. All rights reserved.