ABSTRACT A fundamental goal of human genetics is to decipher the relationship between genotype and phenotype. Genome-wide association studies (GWAS) have identified thousands of common variants associated with numerous traits and diseases; but for the vast majority of genetic associations the underlying functional mechanisms are unknown. The key challenges in elucidating the biology underlying GWAS risk loci are: (i) to identify the susceptibility gene(s) at risk loci and their functional role in disease pathogenesis; (ii) to identify the causal risk variant(s) initiating disease development; and (iii) to establish the regulatory mechanisms by which risk variant(s) affect target gene expression An emerging feature of common variant risk loci is pleiotropy, where a risk locus shows evidence of susceptibility to two or more phenotypes. Breast, prostate and ovarian cancers share common etiologies. GWAS have so far identified more than 400 confirmed risk loci for these cancers. We have performed a meta- analysis of breast, prostate and ovarian cancers identifying more than 100 novel pleiotropic risk regions that suggest these cancers have a shared genetic component and similar underlying biology. Substantially larger genotyping studies continue to be performed in the human population and for these cancers which will provide the opportunity to identify additional breast, prostate and ovarian cancer pleiotropic risk loci. Our groups have also developed functional assays, including chromosome conformation capture, CRISPR/Cas9 genome editing, and experimental models of breast, prostate and ovarian cancer that enables us to establish the underlying biology driving neoplastic development at these risk loci in these cancer types. The overarching goals of this study are to identify shared genetic susceptibility alleles for breast, prostate and ovarian (BPO) cancers driven by non-coding DNA variation, and to establish the shared functional mechanisms that underlie disease risk for these cancers. The specific aims are: (1) To identify the credible causal risk variants, regulatory targets and candidate genes at pleiotropic BPO risk loci; (2) To utilize functional screening assays to prioritize causal risk variants, regulatory targets, and candidate genes at BPO risk loci; (3) To determine causality for risk variants, candidate genes and regulatory elements at BPO risk loci.

PROJECT NARRATIVE Genetic studies have found hundreds of common genetic variations in the population that affect a person’s risk of a multitude of different diseases including cancer but for most of these variants, we neither know the functional reasons why they cause disease, nor the genes they interact with to drive disease development. In this proposal, we plan to use a combination of functional assays, genetic information and computational methods to work out the function of known genetic variants that influence breast, prostate and ovarian cancer risk because these cancers share common risk factors and biology and there are strong reasons to believe that some of the same genes are responsible for causing all three cancer types. We hope these approaches and the methods we use can work out the function of genetic variants and genes that cause disease, leading to clinical benefits to individuals on a population level, particularly in developing new risk prediction and prevention strategies to reduce breast, prostate and ovarian cancer incidence.