Mechanistic insights into genetic susceptibility to prostate cancer

Prostate cancer (PCa) is the second most common cancer in men and is a highly heritable disease that affects millions of individuals worldwide. Genome-wide association studies have to date discovered nearly 270 genetic loci harboring hundreds of single nucleotide polymorphisms (SNPs) that are associated with PCa susceptibility. In contrast, the functional characterization of the mechanisms underlying PCa risk association is still growing. Given that PCa risk-associated SNPs are highly enriched in noncoding cis-regulatory genomic regions, accumulating evidence suggests a widespread modulation of transcription factor chromatin binding and allelic enhancer activity by these noncoding SNPs, thereby dysregulating gene expression. Emerging studies have shown that a proportion of noncoding variants can modulate the formation of transcription factor complexes at enhancers and CTCF-mediated 3D genome architecture. Interestingly, DNA methylation-regulated CTCF binding could orchestrate a long-range chromatin interaction between PCa risk enhancer and causative genes. Additionally, one-causal-variant-two-risk genes or multiple-risk-variant-multiple-genes are prevalent in some PCa risk-associated loci. In this review, we will discuss the current understanding of the general principles of SNP-mediated gene regulation, experimental advances, and functional evidence supporting the mechanistic roles of several PCa genetic loci with potential clinical impact on disease prevention and treatment.