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.

前列腺癌 (PCa) 是男性中第二常见的癌症，是一种高度遗传性疾病，影响着全世界数百万人。迄今为止，全基因组关联研究已发现近 270 个基因位点，其中包含数百个与 PCa 易感性相关的单核苷酸多态性 (SNP)。相比之下，PCa 风险关联机制的功能特征仍在增长。鉴于 PCa 风险相关的 SNP 在非编码顺式中高度富集- 调节基因组区域，越来越多的证据表明这些非编码 SNP 广泛调节转录因子染色质结合和等位基因增强子活性，从而失调基因表达。新兴研究表明，一部分非编码变体可以调节增强子处转录因子复合物的形成和 CTCF 介导的 3D 基因组结构。有趣的是，DNA 甲基化调节的 CTCF 结合可以协调 PCa 风险增强剂和致病基因之间的长程染色质相互作用。此外，一因果变异二风险基因或多风险变异多基因在一些 PCa 风险相关基因座中普遍存在。在这篇综述中，我们将讨论目前对 SNP 介导的基因调控一般原理的理解、实验进展、