Chauhan Pradeep S, Alahi Irfan, Sinha Savar, Ledet Elisa M, Mueller Ryan, Linford Jessica, Shiang Alexander L, Webster Jace, Greiner Lilli, Yang Breanna, Ni Gabris, Dang Ha X, Saha Debanjan, Babbra Ramandeep K, Feng Wenjia, Harris Peter K, Qaium Faridi, Duose Dzifa Y, Alexander Sanchez E, Sherry Alexander D, Jaeger Ellen B, Miller Patrick J, Caputo Sydney A, Orme Jacob J, Lucien Fabrice, Park Sean S, Tang Chad, Pachynski Russell K, Sartor Oliver, Maher Christopher A, Chaudhuri Aadel A
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, Missouri.
Clin Cancer Res. 2025 Jan 6;31(1):151-163. doi: 10.1158/1078-0432.CCR-24-1658.
Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSI) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood.
We applied targeted cell-free DNA (cfDNA) sequencing to 126 patients with mCRPC from three academic cancer centers and separately performed genome-wide cfDNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 patients with mCRPC, respectively, to develop and validate a stem-like signature, which we inferred from cfDNA.
Targeted cfDNA sequencing detected AR/enhancer alterations prior to first-line ARSIs that correlated with significantly worse progression-free survival (P = 0.01; HR = 2.12) and overall survival (P = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (P < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cfDNA revealed enrichment for stemness-associated transcription factors in patients with lethal mCRPC. The resulting stemness signature was then validated in a completely held-out cohort of 80 patients with mCRPC profiled by tumor RNA sequencing.
We analyzed a total of 220 patients with mCRPC, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness. See related commentary by Nawfal et al., p. 7.
对雄激素受体信号抑制剂（ARSI）耐药的转移性去势抵抗性前列腺癌（mCRPC）通常是致命的。针对这种致命疾病形式的液体活检生物标志物仍在研究中，其潜在机制仍未完全了解。
我们对来自三个学术癌症中心的126例mCRPC患者应用了靶向游离DNA（cfDNA）测序，并在一线ARSI治疗开始前对43份血浆样本分别进行了全基因组cfDNA甲基化测序。为了分析全基因组测序数据，我们进行了核小体定位和差异甲基化区域分析。我们还分别分析了14例和80例mCRPC患者的单细胞和批量RNA测序数据，以开发和验证一种从cfDNA推断出的干细胞样特征。
靶向cfDNA测序在一线ARSI治疗前检测到AR/增强子改变，这与无进展生存期显著较差相关（P = 0.01；HR = 2.12）和总生存期相关（P = 0.02；HR = 2.48）。血浆甲基化组分析显示，AR/增强子致死性mCRPC患者的启动子水平低甲基化显著高于AR/增强子野生型mCRPC患者（P < 0.0001）。此外，对cfDNA中核小体更容易接近的转录因子进行基因本体和CytoTRACE分析，发现致死性mCRPC患者中与干性相关的转录因子富集。然后，在一个完全独立的80例通过肿瘤RNA测序分析的mCRPC患者队列中验证了所得的干性特征。
我们共分析了220例mCRPC患者，验证了游离AR/增强子改变作为致命性mCRPC预后生物标志物的重要性，并表明致死的潜在机制涉及将发育状态重编程为增加干性。见Nawfal等人的相关评论，第7页。
