Bechis Seth K, Otsetov Alexander G, Ge Rongbin, Wang Zongwei, Vangel Mark G, Wu Chin-Lee, Tabatabaei Shahin, Olumi Aria F
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
J Urol. 2015 Oct;194(4):1031-7. doi: 10.1016/j.juro.2015.04.079. Epub 2015 Apr 25.
In men with symptomatic benign prostatic hyperplasia 5α-reductase inhibitors are a main modality of treatment. More than 30% of men do not respond to the therapeutic effects of 5α-reductase inhibitors. We have found that a third of adult prostate samples do not express 5α-reductase type 2 secondary to epigenetic modifications. We evaluated whether 5α-reductase type 2 expression in benign prostatic hyperplasia specimens from symptomatic men was linked to methylation of the 5α-reductase type 2 gene promoter. We also identified associations with age, obesity, cardiac risk factors and prostate specific antigen.
Prostate samples from men undergoing transurethral prostate resection were used. We determined 5α-reductase type 2 protein expression and gene promoter methylation status by common assays. Clinical variables included age, body mass index, hypertension, hyperlipidemia, diabetes, prostate specific antigen and prostate volume. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling.
Body mass index and age significantly correlated with methylation of the 5α-reductase type 2 gene promoter (p <0.05) whereas prostate volume, prostate specific antigen or benign prostatic hyperplasia medication did not correlate. Methylation highly correlated with 5α-reductase protein expression (p <0.0001). In a predictive model increasing age and body mass index significantly predicted methylation status and protein expression (p <0.01).
Increasing age and body mass index correlate with increased 5α-reductase type 2 gene promoter methylation and decreased protein expression in men with symptomatic benign prostatic hyperplasia. These results highlight the interplay among age, obesity and gene regulation. Our findings suggest an individualized epigenetic signature for symptomatic benign prostatic hyperplasia, which may be important to choose appropriate personalized treatment options.
在有症状的良性前列腺增生男性患者中，5α还原酶抑制剂是主要的治疗方式。超过30%的男性对5α还原酶抑制剂的治疗效果无反应。我们发现，三分之一的成人前列腺样本由于表观遗传修饰而不表达2型5α还原酶。我们评估了有症状男性的良性前列腺增生标本中2型5α还原酶的表达是否与2型5α还原酶基因启动子的甲基化有关。我们还确定了与年龄、肥胖、心脏危险因素和前列腺特异性抗原的关联。
使用接受经尿道前列腺切除术男性的前列腺样本。我们通过常规检测确定2型5α还原酶蛋白表达和基因启动子甲基化状态。临床变量包括年龄、体重指数、高血压、高脂血症、糖尿病、前列腺特异性抗原和前列腺体积。进行单因素和多因素统计分析，随后进行逐步逻辑回归建模。
体重指数和年龄与2型5α还原酶基因启动子的甲基化显著相关（p<0.05），而前列腺体积、前列腺特异性抗原或良性前列腺增生药物治疗与之无关。甲基化与5α还原酶蛋白表达高度相关（p<0.0001）。在一个预测模型中，年龄增加和体重指数增加显著预测甲基化状态和蛋白表达（p<0.01）。
在有症状的良性前列腺增生男性中，年龄增加和体重指数增加与2型5α还原酶基因启动子甲基化增加和蛋白表达降低相关。这些结果突出了年龄、肥胖和基因调控之间的相互作用。我们的发现提示了有症状良性前列腺增生的个体化表观遗传特征，这对于选择合适的个性化治疗方案可能很重要。
