Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell-free in humans may enable capture of disparate prostate cancer phenotypes. Here, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor binding sites correlated strongly with circulating tumor DNA (ctDNA) fraction—demonstrating capture of prostate cancer-specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinico-genomic features: bone versus liver-predominant disease, serum PSA, biopsy-confirmed histopathological subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential utility for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insight into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool.

中文翻译：

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浆细胞游离 DNA 染色质免疫沉淀分析描述了晚期前列腺癌的表型和临床异质性


细胞表型是前列腺癌表现和治疗耐药性的基础，可以受表观基因组学特征的调节。然而，前列腺癌的嗜骨倾向限制了对转移组织的访问，这意味着大多数先前对前列腺癌染色质生物学的见解都来自临床前模型，这些模型并不能完全代表疾病的复杂性。对人类无浆细胞组中蛋白进行无创染色质免疫沉淀可能能够捕获不同的前列腺癌表型。在这里，我们分析了转移性前列腺癌中 cfDNA 中激活启动子和增强子相关的 H3K4me2，这些 H3K4me2 富含不同的转移模式和不同的临床表现。前列腺癌基因的 H3K4me2 密度、可接近的染色质和谱系定义转录因子结合位点与循环肿瘤 DNA （ctDNA） 组分密切相关——证明捕获了前列腺癌特异性生物学，并为调整 ctDNA 组分的统计框架的开发提供了信息。染色质标志反映了同步测量的临床基因组特征：骨骼与肝脏为主的疾病、血清 PSA、活检证实的组织病理学亚型和 RB1 缺失共同表明沿雄激素受体活性和神经内分泌身份差异轴的表型分离。在特定患者全身治疗连续进展后检测到谱系转换表明个体化耐药监测的潜在效用。转移诱导的正常组织破坏的表观基因组足迹在两名患者的大量 cfDNA 中很明显。最后，使用尚未在前列腺癌中广泛研究的独特染色质标记生成公共表观基因组资源。 这些结果提供了对侵袭性前列腺癌适应性分子景观的见解，并支持血浆 cfDNA 染色质分析作为生物标志物来源和生物发现工具。