Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor (AR)-targeted agents is often lethal. Unfortunately, biomarkers for this deadly disease remain under investigation, and underpinning mechanisms are ill-understood. Here, we applied deep sequencing to ∼100 mCRPC patients prior to the initiation of first-line AR-targeted therapy, which detected AR /enhancer alterations in over a third of patients, which correlated with lethality. To delve into the mechanism underlying why these patients with cell-free AR /enhancer alterations developed more lethal prostate cancer, we next performed genome-wide cell-free DNA epigenomics. Strikingly, we found that binding sites for transcription factors associated with developmental stemness were nucleosomally more accessible. These results were corroborated using cell-free DNA methylation data, as well as tumor RNA sequencing from a held-out cohort of mCRPC patients. Thus, we validated the importance of 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.
medRxiv : the preprint server for health sciences. 2023 Dec 01*** epublish ***
Pradeep S Chauhan, Irfan Alahi, Savar Sinha, Alexander L Shiang, Ryan Mueller, Jace Webster, Ha X Dang, Debanjan Saha, Lilli Greiner, Breanna Yang, Gabris Ni, Elisa M Ledet, Ramandeep K Babbra, Wenjia Feng, Peter K Harris, Faridi Qaium, Ellen B Jaeger, Patrick J Miller, Sydney A Caputo, Oliver Sartor, Russell K Pachynski, Christopher A Maher, Aadel A Chaudhuri