Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) 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 sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA 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 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA.
Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (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 cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing.
We analyzed a total of 220 mCRPC patients, 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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Aug 23 [Epub ahead of print]
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, Alexander Sanchez-Espitia, 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
Mayo Clinic, Rochester, MN, United States., Washington University in St. Louis, St. Louis, MO, United States., Tulane University, New Orleans, LA, United States., Washington University in St. Louis, ST. Louis, MO, United States., Cedars-Sinai Medical Center, United States., Washington University in St. Louis, Saint Louis, MO, United States., Washington University in St. Louis, St. Louis, United States., University of Rochester Medical Center, Rochester, New York, United States., Washington University in St. Louis, Saint Louis, Missouri, United States., The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Tulane University, New Orleans, Louisiana, United States., Ochsner Baptist Medical Center, New Orleans, LA, United States., Mayo Clinic, Rochester, United States., The University of Texas MD Anderson Cancer Center, Houston, tx, United States.