Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA).Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n= 17) and EA (n= 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and EA carcinoma-associated fibroblasts (CAFs) were compared with AA and EA TAS. AA and EA CAFs were treated with demethylating agent 5-Azacytidine (5-AzaC).Results: AA TAS exhibited higher global DNA methylation than EA TAS (p-value < 0.001). Of the 3268 differentially methylated regions identified (DMRs,p-value < 0.05), 85% (2787 DMRs) showed increased DNA methylation in AA TAS, comprising 1648 genes, of which 1379 were protein-coding genes. Based on DNA methylation levels, two AA subgroups were identified. Notably, AA patients with higher DNA methylation were predominantly those with higher Gleason scores. Pathway analysis linked methylated genes in AA TAS to several key signaling pathways (p-value < 0.05), including immune response (e.g., IL-1, IL-15, IL-7, IL-8, IL-3, and chemokine), Wnt/β-catenin, androgen, PTEN, p53, TGF-β, and circadian clock regulation. A total of 168 concordantly methylated genes were identified, with 109 genes (65%) showing increased methylation in AA CAFs and TAS (p-value < 0.05). Treatment with 5-AzaC significantly reduced DNA methylation of concordant genes in AA CAFs (p-value < 0.001).Conclusions: These findings suggest a distinct stromal methylome in AA, providing a foundation for integrating demethylating agents into standard therapies. This approach targets the tumor microenvironment, potentially addressing PCa disparities in AA men.
背景/目的：与非裔美国人相比，前列腺癌在非洲裔美国男性中诊断中位年龄更早、分期更晚且临床结局更差。方法：为探究肿瘤邻近基质中异常DNA甲基化的作用，对17例非裔和15例欧洲裔前列腺癌患者进行了甲基化结合域测序，并通过长散布核元件-1检测独立验证。对非裔和欧裔肿瘤邻近基质中具有统计学显著差异的甲基化基因进行通路分析，并将原代培养的非裔与欧裔癌相关成纤维细胞的DNA甲基化谱与对应种族的肿瘤邻近基质进行比较。使用去甲基化药物5-氮杂胞苷处理两组癌相关成纤维细胞。结果：非裔肿瘤邻近基质整体DNA甲基化水平显著高于欧裔（p值<0.001）。在3268个差异甲基化区域中，85%（2787个区域）在非裔肿瘤邻近基质中呈现甲基化升高，涉及1648个基因（其中1379个为蛋白编码基因）。根据甲基化水平可将非裔患者分为两个亚组，其中高甲基化亚组患者格里森评分普遍较高。通路分析显示非裔肿瘤邻近基质中的甲基化基因与多条关键信号通路显著相关（p值<0.05），包括免疫应答通路（如IL-1、IL-15、IL-7、IL-8、IL-3及趋化因子通路）、Wnt/β-catenin通路、雄激素通路、PTEN通路、p53通路、TGF-β通路及生物钟调控通路。共鉴定出168个一致性甲基化基因，其中109个基因（65%）在非裔癌相关成纤维细胞和肿瘤邻近基质中均呈现甲基化升高（p值<0.05）。5-氮杂胞苷处理可显著降低非裔癌相关成纤维细胞中一致性基因的DNA甲基化水平（p值<0.001）。结论：本研究揭示了非裔人群特有的基质甲基化组特征，为将去甲基化药物整合至标准治疗方案提供了理论基础。这种靶向肿瘤微环境的治疗策略有望改善非裔男性前列腺癌的临床差异。
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