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Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival in AR-altered lethal prostate cancer

Chauhan, P. S.; Alahi, I.; Sinha, S.; Shiang, A. L.; Mueller, R.; Webster, J.; Dang, H. X.; Saha, D.; Greiner, L.; Yang, B.; Ni, G.; Ledet, E. M.; Babbra, R. K.; Feng, W.; Harris, P. K.; Qaium, F.; Jaeger, E. B.; Miller, P. J.; Caputo, S. A.; Sartor, O.; Pachynski, R. K.; Maher, C. A.; Chaudhuri, A. A.

2023-12-01 genetic and genomic medicine
10.1101/2023.12.01.23299215 medRxiv
Show abstract

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.

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