Linkage studies of cancer families have identified high-penetrance cancer genes such as BRCA1 and BRCA2. However, although these genes have resulted in novel insights into cancer, it is clear that a large component of inherited cancer risk remains unacc ounted for. It has been proposed that common low penetrance cancer susceptibility genes contribute significantly to the genetic predisposition of cancer in a polygenic model of inheritance. Association studies have been suggested as the method of choic e for finding susceptibility alleles of high frequency but low penetrance. Here, we propose to take advantage of accumulating genomic data and two European populations of different history and structure to determine the contribution of candidate cancer susceptibility genes to different clinical forms of breast and prostate cancer. We will use a population based association study in Iceland and the Netherlands to map the risk profiles associated with common polymorphic variants in and near candidate c ancer susceptibility genes in breast and prostate cancer patients. We will also develop methods for statistical analysis of complex genomic data which can be used in this and other projects. The proposed study has the potential to cast light on how gen etic variants affect the risk of cancer initiation and how it affects progression and response to treatment. Finally, the results may serve as a starting point for building models of genetic risk of these cancers.
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