Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America.
PLoS One. 2014 Jun 3;9(6):e98597. doi: 10.1371/journal.pone.0098597. eCollection 2014.
Serum microRNAs hold great promise as easily accessible and measurable biomarkers of disease. In prostate cancer, serum miRNA signatures have been associated with the presence of disease as well as correlated with previously validated risk models. However, it is unclear whether miRNAs can provide independent prognostic information beyond current risk models. Here, we focus on a group of low-risk prostate cancer patients who were eligible for active surveillance, but chose surgery. A major criteria for the low risk category is a Gleason score of 6 or lower based on pre-surgical biopsy. However, a third of these patients are upgraded to Gleason 7 on post surgical pathological analysis. Both in a discovery and a validation cohort, we find that pre-surgical serum levels of miR-19, miR-345 and miR-519c-5p can help identify these patients independent of their pre-surgical age, PSA, stage, and percent biopsy involvement. A combination of the three miRNAs increased the area under a receiver operator characteristics curve from 0.77 to 0.94 (p<0.01). Also, when combined with the CAPRA risk model the miRNA signature significantly enhanced prediction of patients with Gleason 7 disease. In-situ hybridizations of matching tumors showed miR-19 upregulation in transformed versus normal-appearing tumor epithelial, but independent of tumor grade suggesting an alternative source for the increase in serum miR-19a/b levels or the release of pre-existing intracellular miR-19a/b upon progression. Together, these data show that serum miRNAs can predict relatively small steps in tumor progression improving the capacity to predict disease risk and, therefore, potentially drive clinical decisions in prostate cancer patients. It will be important to validate these findings in a larger multi-institutional study as well as with independent methodologies.
血清 microRNAs 作为疾病的易于获取和测量的生物标志物具有巨大的应用前景。在前列腺癌中，血清 miRNA 特征与疾病的存在相关，并且与先前验证的风险模型相关。然而，miRNAs 是否可以提供超出当前风险模型的独立预后信息尚不清楚。在这里，我们重点关注一组有资格接受主动监测但选择手术的低危前列腺癌患者。低危类别的主要标准是基于术前活检的 Gleason 评分 6 或更低。然而，其中三分之一的患者在术后病理分析中升级为 Gleason 7。在发现和验证队列中，我们发现术前血清 miR-19、miR-345 和 miR-519c-5p 的水平可以帮助识别这些患者，而与他们的术前年龄、PSA、分期和活检受累百分比无关。三种 miRNA 的组合将接收者操作特征曲线下的面积从 0.77 增加到 0.94（p<0.01）。此外，当与 CAPRA 风险模型结合时，miRNA 特征显著增强了对 Gleason 7 疾病患者的预测。匹配肿瘤的原位杂交显示转化肿瘤中 miR-19 的上调，而与肿瘤分级无关，提示血清 miR-19a/b 水平升高或进展时细胞内 miR-19a/b 的释放有替代来源。这些数据表明，血清 miRNAs 可以预测肿瘤进展的相对较小步骤，从而提高预测疾病风险的能力，从而有可能为前列腺癌患者的临床决策提供依据。在更大的多机构研究以及独立的方法学中验证这些发现将非常重要。
