Analysis of breast cancer risk modifying candidate genes in BRCA1 and BRCA2 mutation carriers

1317 Marked variability in individual cancer risk has been observed among BRCA1/2 mutation carriers, both between and within families. While some of this difference may result from the respective methodological approaches, it is likely that the observed variation is due to other genetic and/or environmental modifying factors that affect individual risk. Lifestyle events such as parity and oral contraceptive use alter breast / ovarian cancer risk. Mutation penetrance in the BRCA genes may also vary depending on the presence of specific alleles of a genetic modifier. Identification of such variants will provide good candidates to test as low penetrance predisposing genes in general. We are using association studies to assess the influence of variants (mainly SNPs) in biologically plausible candidate loci on the penetrance of BRCA1/2 mutations (i.e., differences in age of onset or tissue-specificity of disease) from the breast / ovarian cancer families characterised from our laboratories. We are focusing on typing SNPs in several DNA repair genes previously examined as modifier loci or as breast cancer susceptibility alleles in general, and from genes whose protein products interact with the BRCA proteins. The SNPs are typed in around 1000 BRCA1/2 mutation carriers from our families by TaqmanTM (ABI) using the ABI Prism 3700 Sequence Detection System. The first statistical analysis of our genotype data concern common polymorphisms in the BRCA2 genes (203G>A and N372H). These SNPs were previously tested as breast cancer susceptibility alleles in general by Healey and colleagues (2000). We tested these alleles as potential modifiers of breast cancer penetrance in our 656 BRCA1 mutation carriers but found no evidence of a modifying effect. Adjusting for age of birth and parity or stratifying by family did not significantly alter these results. In contrast to the result of Healey et al (2000) on newborn females and adult female controls, we found no departure from HW equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. An understanding of the modifying effects on breast cancer risk in BRCA1/2 mutation carriers should help refine individual risk estimates. The discovery of BRCA1/2 modifiers may clarify our functional understanding of these genes. Many of these modifiers may themselves be moderate to low penetrance predisposing genes in general.