A substantial proportion of familial aggregation of breast cancer is likely to be due to "low-risk" genetic factors. Are common but subtle functional variants in genes likely to be involved in cancer predisposition. Genes of interest include those mediating a range of functions such as steroid hormone metabolism, cell cycle control and DNA repair. To date many studiers have investigated the role of genes involved in steroid metabolism, but the role of DNA repair genes is unknown. We intend to carry our two parallel population-based breast cancer-control comparisons using Australian and Canadian subjects from the Cooperative Family Registry for Breast Cancer Studies (CFRBCS) for a number of genetic variants involved in DNA repair. Each will be contributing about 1,500 cases and 750 unaffected controls, frequency matched for age- and ethnicity. For polymorphisms in which an association with breast cancer risk is found in a case-control comparison in one site, we will test the association using the material of the other site, and extend the study to a family-based design using 2,209 nuclear families (4,450 family members in total) from all three population-based sites of the CFRBCS. If associations with breast cancer risk are confirmed using these complementary methods in independent samples, it will provide strong evidence that the association is not a false positive due to multiple comparisons or selective reporting. This will lead to a better understanding of breast cancer etiology and may have important clinical implications for screening and disease prevention. The large scale of this study allows us to test recessive, as well as dominant, models with reasonable power. In addition, the availability of genotypic information for many candidate genes (in steroid hormone metabolism as well as DNA repair) will ultimately allow for the assessment of interactions between genes of different pathways. Furthermore, the availability of extensive epidemiological data will allow us to determine if specific genotypes of putative predisposition genes interact with certain environmental exposures such as radiation exposure.