This is a revision of a competitive renewal of an existing funded project to identify prostate cancer (PCa) risk enhancers and their target genes. We intend to identify all target genes affected by newly identified enhancers that contain genetic variation at 77 known PCa risk loci. The major `problem' of genome-wide association (GWAS) loci is the lack of mechanistic understanding of how risk alleles function. This is exacerbated by the fact that the vast majority (>90% of PCa risk alleles) resides in non-coding DNA such as enhancers. This application therefore intends to systematically identify target genes of all the newly identified PCa risk enhancers using three independent approaches, formulated here as three specific aims under the auspices of three co-PIs. The three aims are: eQTL (Coetzee) to link SNP genotypes with levels of gene expression genome-wide, CRISPRs (Farnham) to edit enhancers in situ (deletion and allelic replacement) linking them with gene expression and finally 4C (Lu) to match enhancers with potential target genes by chromatin conformation capture. The strength of this plan is that common target genes identified by all three approaches are likely to be functionally significant. Results will elucidate previously unanticipated risk mechanisms and will provide rationale for diagnosis and prevention.
Over the last few years 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 heart disease, diabetes and cancer. In the present project we intend to build on work done in the previous grant cycle to identify genes involved in prostate cancer risk. We hope that the data to be acquired will inform preventive and clinical benefits to individuals at risk.
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