ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
Genomic and Epigenomic Analysis of Plasma Cell-Free DNA Identifies Stemness Features Associated with Worse Survival in Lethal Prostate Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Evolution of AR and Non-AR Alterations in ctDNA of Patients with Metastatic Prostate Cancer Treated in the Phase III Alliance A031201 Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Multi-omics-driven precision medicine.iMeta · 2026Review
- Increasing Cancer Stemness Drives Prostate Cancer Progression, Plasticity, Therapy Resistance and Poor Patient Survival.bioRxiv : the preprint server for biology · 2026Article
- AR and Beyond: ctDNA Maps Resistance Evolution in mCRPC.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Review
- Integrative dual ctDNA 5mC/5hmC methylomics and clonal reconstruction infer tumor transcription and resistance phenotypes in metastatic prostate cancer.Research square · 2026Article
- Plasma epigenomic profiling reveals treatment-emergent squamous transformation in prostate cancer.NPJ precision oncology · 2025Article
- Advances in genomic biomarkers for lethal metastatic castration-resistant prostate cancer.Translational cancer research · 2025Article
- Review
- Systems-level liquid biopsy in advanced prostate cancer.Endocrine-related cancer · 2025Review
- Bone metastases from endocrine cancer: advances in diagnosis, treatment, and prevention.Frontiers in endocrinology · 2025Review
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Abstract
purposeMetastatic 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
designWe 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.
resultsTargeted 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.
conclusionsWe 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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