Chauhan Pradeep S, Alahi Irfan, Sinha Savar, Shiang Alexander L, Mueller Ryan, Webster Jace, Dang Ha X, Saha Debanjan, Greiner Lilli, Yang Breanna, Ni Gabris, Ledet Elisa M, Babbra Ramandeep K, Feng Wenjia, Harris Peter K, Qaium Faridi, Jaeger Ellen B, Miller Patrick J, Caputo Sydney A, Sartor Oliver, Pachynski Russell K, Maher Christopher A, Chaudhuri Aadel A
medRxiv. 2023 Dec 1:2023.12.01.23299215. doi: 10.1101/2023.12.01.23299215.
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 /enhancer alterations in over a third of patients, which correlated with lethality. To delve into the mechanism underlying why these patients with cell-free /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 /enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.
对雄激素受体（AR）靶向药物耐药的转移性去势抵抗性前列腺癌（mCRPC）往往是致命的。不幸的是，针对这种致命疾病的生物标志物仍在研究中，其潜在机制也尚未完全了解。在此，我们在一线AR靶向治疗开始前，对约100例mCRPC患者进行了深度测序，结果在超过三分之一的患者中检测到了/增强子改变，且这些改变与致死率相关。为深入探究为何这些有无细胞/增强子改变的患者会发展出更具致命性的前列腺癌，接下来我们进行了全基因组无细胞DNA表观基因组学研究。令人惊讶的是，我们发现与发育干性相关的转录因子结合位点在核小体上更容易接近。使用无细胞DNA甲基化数据以及来自一组未参与研究的mCRPC患者的肿瘤RNA测序结果，证实了这些结果。因此，我们验证了/增强子改变作为致命性mCRPC预后生物标志物的重要性，并表明致死的潜在机制涉及将发育状态重编程为增加干性。
