Discovery of Novel Protein Biomarkers in Urine for Diagnosis of Urothelial Cancer

Urothelial carcinoma (UC) is the ninth most prevalent malignancy worldwide. Noninvasive and efficient biomarkers with high accuracy are imperative for the surveillance and diagnosis of UC. CKD patients were enrolled as a control group in this study for the discovery of highly specific urinary protein markers of UC. An iTRAQ-labeled quantitative proteomic approach was used to discover novel potential markers. These markers were further validated with 501 samples by ELISA assay, and their diagnostic accuracies were compared to those of other reported UC markers. BRDT, CYBP, GARS, and HDGF were identified as novel urinary UC biomarkers with a high discrimination ability in a population comprising CKD and healthy subjects. The diagnostic values of the four novel UC markers were better than that of a panel of well-known or FDA-approved urinary protein markers CYFR21.1, Midkine, and NUMA1. Three of our discovered markers (BRDT, HDGF, GARS) and one well-known marker (CYFR21.1) were finally selected and combined as a marker panel having AUC values of 0.962 (95% CI, 0.94−0.98) and 0.860 (95% CI, 0.83−0.89) for the discrimination between UC and normal groups and UC and control (healthy + CKD) groups, respectively.

泌尿道上皮細胞癌 (UC) 是全球第九大最常見的惡性腫瘤。目前泌尿道上皮細胞癌的監測和診斷仍欠缺非侵入性與高準確的生物標誌物。此研究中，納入健康人、慢性腎病變患者為控制組，在泌尿道上皮細胞癌病人尿液中去探索高度特異性蛋白標誌物。使用 iTRAQ 標記的定量蛋白質組學方法發現新的潛在標誌物。這些標誌物通過 ELISA 測定對 501 個樣本進行了進一步驗證，並將其診斷準確性與其它已報導的生物標誌物進行了比較。結果顯示BRDT、CYBP、GARS 和 HDGF 被鑑定為新型尿液泌尿道上皮細胞癌生物標誌，在包括慢性腎病變和健康受試者的人群中具有高度區辨能力。四種新型泌尿道上皮細胞癌標誌物的準確度優於已知或FDA 批准的尿液蛋白標誌物 CYFR21.1、Midkine 和 NUMA1。我們發現的三個標記（BRDT、HDGF、GARS）和一個已知的癌症標記（CYFR21.1）可以組合成一個極高準確度的生物標誌組以用於區辨泌尿道上皮細胞癌和健康群組(AUC:0.962, 95% CI, 0.94-0.98）以及泌尿道上皮細胞癌和控制組（健康與慢性腎病變）(AUC:0.860, 95 % CI, 0.83-0.89）。