Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava

Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.

伴有瘤栓（tumor thrombus, TT）侵犯下腔静脉（inferior vena cava, IVC）的透明细胞肾细胞癌（Clear cell renal cell carcinoma, ccRCC）通常提示不良预后。然而，肾切除术联合血栓切除术后的肿瘤复发风险存在显著异质性。目前亟需一款适用且精准的预测系统，以筛选出肾切除术后复发风险较高的下腔静脉瘤栓型透明细胞肾细胞癌（ccRCC/TT）患者，但此类系统至今尚未建立。据我们所知，目前尚未探索微小RNA（microRNAs, miRs）在ccRCC/TT发生发展中的潜在作用，亦未明确其作为ccRCC/TT预后标志物的价值。为此，我们纳入74例ccRCC患者作为研究队列，分析了8种已被报道的致癌微小RNA（onco-miRs）的表达水平，分别为miR-200c、miR-210、miR-126、miR-221、let-7b、miR-21、miR-143及miR-141。基于这8种miRs的表达谱，我们构建了分类系统，可精准区分ccRCC与非癌性肾组织，以及ccRCC/TT与无瘤栓的肾细胞癌病灶。在37例ccRCC/TT患者的亚组分析中，我们发现miR-21、miR-126及miR-221可独立于其他临床病理特征，精准预测癌症相关死亡（cancer related death, CRD）。此外，我们基于miR-21、miR-126及miR-221的表达水平构建了联合风险评分（combined risk score, CRS），该评分在预测ccRCC/TT患者的癌症特异性生存（cancer specific survival, CSS）时展现出较高的灵敏度与特异度。借助该联合风险评分，我们可将ccRCC/TT患者准确划分为高风险与低风险两个亚组。该联合风险评分的风险分层体系仍需进一步队列验证，但其有望作为一款分子预测系统，用于识别高风险ccRCC/TT患者，具备潜在的临床应用价值。