Mizuno Kei, Ku Sheng-Yu, Venkadakrishnan Varadha Balaji, Bakht Martin K, Sigouros Michael, Chan Joanna, Trigos Anna, Driskill Jordan H, Manohar Jyothi, King Abigail, Presser Adam G, Kim Min Jin, Tewari Alok K, Long Henry W, Quigley David, Choueiri Toni K, Balk Steven, Hill Sarah, Mosquera Juan Miguel, Einstein David, Sandhu Shahneen, Taplin Mary-Ellen, Beltran Himisha
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
Nat Commun. 2025 Jul 1;16(1):5543. doi: 10.1038/s41467-025-60654-z.
Castration-resistant prostate cancer is a heterogeneous disease with variable phenotypes commonly observed in later stages of the disease. These include cases that retain expression of luminal markers and those that lose hormone dependence and acquire neuroendocrine features. While there are distinct transcriptomic and epigenomic differences between castration-resistant adenocarcinoma and neuroendocrine prostate cancer, the extent of overlap and degree of diversity across tumor metastases in individual patients has not been fully characterized. Here we perform combined DNA methylation, RNA-sequencing, H3K27ac, and H3K27me3 profiling across metastatic lesions from patients with CRPC/NEPC. Integrative analyses identify DNA methylation-driven gene links based on location (H3K27ac, H3K27me3, promoters, gene bodies) pointing to mechanisms underlying dysregulation of genes involved in tumor lineage (ASCL1, AR) and therapeutic targets (PSMA, DLL3, STEAP1, B7-H3). Overall, these data highlight how integration of DNA methylation with RNA-sequencing and histone marks can inform intraindividual epigenetic heterogeneity and identify putative mechanisms driving transcriptional reprogramming in castration-resistant prostate cancer.
去势抵抗性前列腺癌是一种异质性疾病，在疾病后期通常会观察到多种不同的表型。这些表型包括保留管腔标志物表达的病例以及那些失去激素依赖性并获得神经内分泌特征的病例。虽然去势抵抗性腺癌和神经内分泌前列腺癌之间存在明显的转录组和表观基因组差异，但个体患者肿瘤转移灶之间的重叠程度和多样性程度尚未得到充分表征。在此，我们对CRPC/NEPC患者的转移病灶进行了DNA甲基化、RNA测序、H3K27ac和H3K27me3联合分析。综合分析基于位置（H3K27ac、H3K27me3、启动子、基因体）确定了DNA甲基化驱动的基因联系，这些联系指向肿瘤谱系（ASCL1、AR）和治疗靶点（PSMA、DLL3、STEAP1、B7-H3）中涉及的基因失调的潜在机制。总体而言，这些数据突出了DNA甲基化与RNA测序和组蛋白标记的整合如何能够揭示个体内表观遗传异质性，并确定驱动去势抵抗性前列腺癌转录重编程的潜在机制。
