Wong Jodie, Tian Yijun, Patel Manishkumar S, Avasthi Kapil, Hanson Claire, Larsen Matt, Ampaw Enos, Fadlullah Muhammad Z H, Finklestein Joseph, Tan Aik Choon, Park Jong, Manley Brandon J, Huang Chiang-Ching, Kohli Manish, Wang Liang
H. Lee Moffitt Cancer Center.
University of Utah, Huntsman Cancer Institute.
Res Sq. 2025 Apr 21:rs.3.rs-6331572. doi: 10.21203/rs.3.rs-6331572/v1.
Molecular prognostication in metastatic castration prostate cancer (mCRPC) remains challenging due to the lack of validated biomarkers. This study developed a plasma cell-free DNA (cfDNA) methylation-based prognostic model in mCRPC. Targeted cfDNA methylation sequencing in 96 prostate cancer patients in different states of cancer progression revealed 78 methylation haplotype blocks (MHBs) differentially methylated from organ-confined prostate cancer to mCRPC states. Among these 78 MHBs, the top 20 MHBs were associated with mCRPC overall survival and most MHB methylation levels positively correlated with predicted circulating tumor DNA (ctDNA) fraction. By integrating the MHB-based risk score with currently available prognostic clinical variables and ctDNA fraction a prognostic nomogram was developed which showed high predictive performance for mCRPC survival (AUC = 0.99 for 6 months, AUC = 0.90 for 1 year, and AUC = 0.87 for 2 years). These findings demonstrate potential of cfDNA methylation as a molecular biology-driven biomarker for mCRPC prognosis.
由于缺乏经过验证的生物标志物，转移性去势抵抗性前列腺癌（mCRPC）的分子预后评估仍然具有挑战性。本研究在mCRPC中开发了一种基于血浆游离DNA（cfDNA）甲基化的预后模型。对96例处于不同癌症进展状态的前列腺癌患者进行靶向cfDNA甲基化测序，发现从器官局限性前列腺癌到mCRPC状态有78个甲基化单倍型模块（MHBs）存在差异甲基化。在这78个MHBs中，前20个MHBs与mCRPC总生存期相关，且大多数MHB甲基化水平与预测的循环肿瘤DNA（ctDNA）分数呈正相关。通过将基于MHB的风险评分与现有的预后临床变量和ctDNA分数相结合，开发了一种预后列线图，该列线图对mCRPC生存具有较高的预测性能（6个月时AUC = 0.99，1年时AUC = 0.90，2年时AUC = 0.87）。这些发现证明了cfDNA甲基化作为mCRPC预后的分子生物学驱动生物标志物的潜力。
