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posted on 2025-01-06, 08:20 authored by 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 Supplementary Figure S5. Kaplan-Meier survival analysis based on plasma collected prior to first-line androgen receptor-signaling inhibitor (ARSI) treatment in 63 mCRPC patients according to (A,B) PTEN copy number loss status in cfDNA, (C,D) PTEN copy number loss or mutation in cfDNA, and (E,F) alteration in AR/Enhancer or PTEN in cfDNA. p values were calculated by the log-rank test and hazard ratios (HRs) by the Mantel-Haenszel method. cfDNA, cell-free DNA; mCRPC; metastatic castration-resistant prostate cancer.
Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
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V Foundation for Cancer Research (VFCR)
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ARTICLE ABSTRACT
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
