SUMMARY
Although the causes of human cancers are attributable to many factors, there is substantial evidence that
genetics likely plays a key role. Previous studies have used population-based approaches, such as genome-
wide association studies (GWASs), to identify cancer-associated genetic susceptibility variants (single nucleotide
polymorphisms or SNPs) in the human genome. Although GWASs have reported thousands of SNP loci
associated with an increased cancer risk, functional effects of these risk-SNPs remain largely unknown. Because
many of the risk-SNPs are located in genomic regions without known protein-coding genes and some reside
several hundred kilobases from any nearby gene, it is believed that many, if not most, of these SNPs have
regulatory effects on the genes that cause these cancers. To identify regulatory SNPs responsible for the disease
risk, we propose to apply two novel high-throughput sequencing technologies to screen thousands of candidate
SNPs at prostate cancer risk loci. Aim 1 is to determine SNP-dependent transcription factor (TF) binding
differences at prostate cancer risk loci through IP-SNPs-seq. Aim 2 is to determine biological significance of
SNP-dependent sequence variants at prostate cancer risk loci through CRISPRi-SNPs-seq. Aim 3 is to
functionally characterize a set of selected SNPs and their target genes. Successful completion of the proposed
study will gain further understanding of the functional role of GWAS-implicated SNPs. Characterization of the
functional effects of cancer risk loci will facilitate the translation of population-based discovery into biological
mechanisms and will eventually benefit clinical practice.
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