Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China.
Department of Urology, The Eighth People's Hospital of Shanghai, 8 Caobao Road, Shanghai, 200235, China.
BMC Med. 2022 Aug 25;20(1):270. doi: 10.1186/s12916-022-02467-1.
There are no proven tumor biomarkers for the early diagnosis of clear cell renal cell carcinoma (ccRCC) thus far. This study aimed to identify novel biomarkers of ccRCC based on exosomal mRNA (emRNA) profiling and develop emRNA-based signatures for the early detection of ccRCC.
Four hundred eighty-eight participants, including 226 localized ccRCCs, 73 patients with benign renal masses, and 189 healthy controls, were recruited. Circulating emRNA sequencing was performed in 12 ccRCCs and 22 healthy controls in the discovery phase. The candidate emRNAs were evaluated with 108 ccRCCs and 70 healthy controls in the test and training phases. The emRNA-based signatures were developed by logistic regression analysis and validated with additional cohorts of 106 ccRCCs, 97 healthy controls, and 73 benign individuals.
Five emRNAs, CUL9, KMT2D, PBRM1, PREX2, and SETD2, were identified as novel potential biomarkers of ccRCC. We further developed an early diagnostic signature that comprised KMT2D and PREX2 and a differential diagnostic signature that comprised CUL9, KMT2D, and PREX2 for RCC detection. The early diagnostic signature displayed high accuracy in distinguishing ccRCCs from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.836 and 0.830 in the training and validation cohorts, respectively. The differential diagnostic signature also showed great performance in distinguishing ccRCCs from benign renal masses (AUC = 0.816), including solid masses (AUC = 0.810) and cystic masses (AUC = 0.832).
We established and validated novel emRNA-based signatures for the early detection of ccRCC and differential diagnosis of uncertain renal masses. These signatures could be promising and noninvasive biomarkers for ccRCC detection and thus improve the prognosis of ccRCC patients.
目前尚无明确用于早期诊断肾透明细胞癌（ccRCC）的肿瘤生物标志物。本研究旨在基于外泌体 mRNA（emRNA）谱鉴定 ccRCC 的新型生物标志物，并开发用于早期检测 ccRCC 的 emRNA 标志物。
纳入 488 名患者，包括 226 例局限性 ccRCC、73 例肾良性肿块患者和 189 名健康对照者。在发现阶段对 12 例 ccRCC 患者和 22 名健康对照者进行循环 emRNA 测序。在测试和训练阶段，对 108 例 ccRCC 患者和 70 名健康对照者进行候选 emRNA 评估。采用逻辑回归分析开发 emRNA 标志物，并通过另外的 106 例 ccRCC 患者、97 名健康对照者和 73 例良性个体验证。
鉴定出 5 个 emRNA，CUL9、KMT2D、PBRM1、PREX2 和 SETD2，作为 ccRCC 的新型潜在生物标志物。进一步开发了一个早期诊断标志物，包含 KMT2D 和 PREX2；开发了一个差异诊断标志物，包含 CUL9、KMT2D 和 PREX2，用于检测 RCC。早期诊断标志物在区分 ccRCC 与健康对照者方面具有较高的准确性，在训练和验证队列中，受试者工作特征曲线下面积（AUC）分别为 0.836 和 0.830。差异诊断标志物在区分 ccRCC 与肾良性肿块（AUC=0.816）方面也表现出良好的性能，包括实性肿块（AUC=0.810）和囊性肿块（AUC=0.832）。
本研究建立并验证了用于早期检测 ccRCC 和鉴别不确定肾肿块的新型 emRNA 标志物。这些标志物可能是检测 ccRCC 的有前景的非侵入性生物标志物，从而改善 ccRCC 患者的预后。
