Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

雄激素受体 (AR) 驱动前列腺癌 (PCa) 的发展和进展。AR 染色质结合谱具有高度可塑性，并形成可区分疾病阶段、亚型和患者结果的反复程序性变化。虽然之前的研究侧重于患者亚组之间的一致性，但 AR 增强剂选择性的肿瘤间异质性仍未得到探索。在这里，我们报告了人类原发性前列腺肿瘤中高水平的 AR 染色质结合异质性，这与在健康前列腺上皮细胞中观察到的异质性重叠。这种异质性具有功能性后果，因为体细胞突变会聚在原发性转移组织中的共同 AR 位点上。相比之下，较少共享的 AR 位点与 AR 驱动的基因表达密切相关，而这种异质性 AR 增强剂的使用也可以区分患者的结果。这些发现表明，原发疾病的表观遗传异质性可直接提供生化复发风险的信息。总的来说，我们的结果说明了原发性 PCa 中 AR 增强子的高度异质性驱动差异表达和临床影响。