Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Department of Histopathology, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Int J Mol Sci. 2017 Sep 20;18(9):2017. doi: 10.3390/ijms18092017.
Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer (PC) due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 () promoter methylation and RNA expression levels for PC. Initially, by quantitative methylation specific PCR (qMSP) analysis of a large radical prostatectomy (RP) cohort ( = 292), we found that the promoter was significantly hypomethylated in PC compared to non-malignant (NM) prostate tissue samples ( < 0.001) with an AUC (area under the curve) of 0.908 by receiver operating characteristics (ROC) curve analysis. Moreover, significant promoter hypomethylation ( ≤ 0.010) as well as overexpression ( < 0.001) was found in PC samples from another large independent patient sample set (498 PC vs. 67 NM) analyzed by Illumina 450K DNA methylation arrays and/or RNA sequencing. promoter methylation and transcriptional expression levels were inversely correlated, suggesting that epigenetic mechanisms contribute to the regulation of gene activity. Furthermore, low TFF3 expression was significantly associated with high ERG, ETS transcription factor (ERG) expression ( < 0.001), as well as with high Gleason score ( < 0.001), advanced pathological T-stage ( < 0.001), and prostate-specific antigen (PSA) recurrence after RP ( = 0.013; univariate Cox regression analysis). There were no significant associations between promoter methylation levels, ERG status, or PSA recurrence in these RP cohorts. In conclusion, our results demonstrated diagnostic biomarker potential of promoter hypomethylation for PC as well as prognostic biomarker potential of TFF3 RNA expression. To the best of our knowledge, this is the most comprehensive study of promoter methylation and transcriptional expression in PC to date.
临床上，由于诊断和预后工具不理想，前列腺癌（PC）中具有临床意义的肿瘤的过度诊断和过度治疗仍然是一个主要问题。因此，迫切需要新的生物标志物。在这项研究中，我们研究了三叶因子 3（）启动子甲基化和 RNA 表达水平在前列腺癌中的生物标志物潜力。最初，通过对大量根治性前列腺切除术（RP）队列（= 292）的定量甲基化特异性 PCR（qMSP）分析，我们发现与非恶性（NM）前列腺组织样本相比，PC 中 启动子明显低甲基化（<0.001），ROC 曲线分析的 AUC（曲线下面积）为 0.908。此外，在另一个由 498 例 PC 与 67 例 NM 患者样本组成的独立患者样本集（经 Illumina 450K DNA 甲基化芯片和/或 RNA 测序分析）中，发现显著的 启动子低甲基化（≤0.010）和过表达（<0.001）。启动子甲基化和转录表达水平呈负相关，表明表观遗传机制有助于基因活性的调节。此外，TFF3 表达水平低与 ERG、ETS 转录因子（ERG）表达水平高（<0.001）、Gleason 评分高（<0.001）、病理 T 期高（<0.001）和前列腺特异性抗原（PSA）复发后 RP（=0.013；单变量 Cox 回归分析）显著相关。在这些 RP 队列中，没有发现 启动子甲基化水平、ERG 状态或 PSA 复发之间的显著相关性。总之，我们的研究结果表明，与 PC 相比，启动子低甲基化具有诊断生物标志物潜力，而 TFF3 RNA 表达具有预后生物标志物潜力。据我们所知，这是迄今为止对 PC 中 启动子甲基化和转录表达最全面的研究。
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