Genomic and Epigenomic Analysis of Plasma Cell-Free DNA Identifies Stemness Features Associated with Worse Survival in Lethal Prostate Cancer.

IF 10 1区医学 Q1 ONCOLOGY

Clinical Cancer Research Pub Date : 2025-01-06 DOI:10.1158/1078-0432.CCR-24-1658

Pradeep S Chauhan, Irfan Alahi, Savar Sinha, Elisa M Ledet, Ryan Mueller, Jessica Linford, Alexander L Shiang, Jace Webster, Lilli Greiner, Breanna Yang, Gabris Ni, Ha X Dang, Debanjan Saha, Ramandeep K Babbra, Wenjia Feng, Peter K Harris, Faridi Qaium, Dzifa Y Duose, Sanchez E Alexander, Alexander D Sherry, Ellen B Jaeger, Patrick J Miller, Sydney A Caputo, Jacob J Orme, Fabrice Lucien, Sean S Park, Chad Tang, Russell K Pachynski, Oliver Sartor, Christopher A Maher, Aadel A Chaudhuri

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引用次数: 0

Abstract

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: 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.

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血浆细胞游离 DNA 的基因组和表观基因组分析确定了与致死性前列腺癌生存率下降相关的干性特征。

目的：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）往往是致命的。这种致命疾病的液体生物标志物仍在研究中，其基本机制仍不清楚：我们对来自三个癌症学术中心的126名mCRPC患者进行了无细胞DNA靶向测序，并对一线ARSI治疗开始前收集的43份血浆样本分别进行了全基因组无细胞DNA甲基化测序。为了分析全基因组测序数据，我们进行了核糖体定位和差异甲基化区域分析。此外，我们还分析了分别来自14名和80名mCRPC患者的单细胞和大量RNA测序数据，以开发并验证从无细胞DNA中推断出的干样特征：结果：靶向无细胞DNA测序检测到一线ARSI之前的AR/增强子改变，这与PFS（p = 0.01；HR = 2.12）和OS（p = 0.02；HR = 2.48）显著恶化相关。血浆甲基组分析显示，AR/增强子致死型mCRPC患者的启动子水平低甲基化程度明显高于AR/增强子野生型mCRPC患者（p < 0.0001）。此外，基因本体论和CytoTRACE对细胞游离DNA中核糖体可访问转录因子的分析表明，致死型mCRPC患者的干性相关转录因子富集。随后，在通过肿瘤RNA测序分析的80名mCRPC患者队列中验证了由此得出的干性特征：我们对220名mCRPC患者进行了分析，验证了细胞游离AR/增强子改变作为致死性mCRPC预后生物标志物的重要性，并表明致死性的根本机制涉及向干性增强方向重编程发育状态。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.