Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity. Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity. Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT. A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

中文翻译：

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一种新的 DNA 甲基化特征与骨转移性前列腺癌的雄激素受体活性和患者预后相关


转移性前列腺癌 (PC) 患者接受雄激素剥夺疗法 (ADT) 治疗，最初可减少转移生长，但一段时间后会出现致命的去势抵抗性 PC (CRPC)。需要更好地了解骨转移中的肿瘤生物学，以指导进一步的治疗开发。我们的研究团队之前已经根据转录组分析确定了 PC 骨转移的亚组，具体而言，已经描述了与雄激素受体 (AR) 活性相关的异质性。 PC 进展过程中的表观遗传改变仍然难以捉摸，本研究旨在探索与基因表达和肿瘤 AR 活性相关的启动子基因甲基化特征。总共 94 个肿瘤样本的全基因组启动子相关 CpG 甲基化特征，包括源自根治性前列腺切除术样本的配对非恶性和恶性原发肿瘤区域 (n = 12)，以及未接受激素治疗的单独患者的骨转移样本 (使用 Infinium 甲基化 EPIC 阵列对 n = 14）、短期去势 (n = 4) 或 CRPC (n = 52) 疾病进行分析，并使用 Illumina Bead Chip 阵列进行基因表达分析 (n = 90)。 AR 活性是根据与典型 AR 活性相关的基因的表达水平来定义的。综合表观基因组和转录组分析发现，与局部前列腺肿瘤的非恶性区域相比，恶性区域存在明显的高甲基化。转移灶显示出与原发性 PC 相关的整体低甲基化，包括 AR 启动子中的 CpG，并伴有 AR mRNA 水平的诱导。 我们确定了雄激素受体活性 (MCA) 特征的甲基化分类器，它将转移分为与肿瘤特征和患者预后相关的两个簇（MCA 阳性/阴性）。 MCA 阳性转移灶显示与经典 AR 信号相关的基因甲基化水平较低，ADT 后患者的预后更为良好。相比之下，MCA 阴性患者的 AR 活性较低，与 AR 相关基因的高甲基化相关，ADT 后预后较差。启动子甲基化特征将 PC 骨转移分为两组，并预测 ADT 后肿瘤 AR 活性和患者预后。对 PC 进展过程中观察到的甲基化多样性的解释及其生物学和临床相关性需要进一步探索。