Urine-based testing is promising for noninvasive diagnosis of urothelial carcinoma (UC) but has suboptimal sensitivity for early-stage tumors. Herein, we developed a multitarget urine tumor DNA test, UI-Seek, for UC detection and evaluated its clinical feasibility. The prediction model was developed in a retrospective cohort (n = 382), integrating assays for FGFR3 and TERT mutations and aberrant ONECUT2 and VIM methylation to generate a UC-score. The test performance was validated in a double-blinded, multicenter, prospective trial (n = 947; ChiCTR2300076543) and demonstrated a sensitivity of 91.37% and a specificity of 95.09%. The sensitivity reached 75.81% for low-grade Ta tumors and exceeded 93% in high-grade Ta and higher stages (T1 to T4). Simultaneous identification of both bladder and upper urinary tract tumors was enabled with sensitivities exceeding 90%. No significant confounding effects were observed regarding benign urological diseases or non-UC malignancies. The test showed improved sensitivities over urine cytology, the NMP22 test, and UroVysion FISH alongside comparable specificities. The single-target accuracy was greater than 98% as confirmed by Sanger sequencing. Post-surgery UC-score decreased in 97.7% of subjects. Overall, UI-Seek demonstrated robust performance and considerable potential for the early detection of UC.

中文翻译：

---

多靶点尿液 DNA 检测用于尿路上皮癌检测的临床有效性：双盲、多中心、前瞻性试验

基于尿液的检测有望用于尿路上皮癌 (UC) 的无创诊断，但对早期肿瘤的敏感性不佳。在此，我们开发了一种用于 UC 检测的多靶点尿液肿瘤 DNA 检测 UI-Seek，并评估了其临床可行性。该预测模型是在回顾性队列 (n = 382) 中开发的，整合了 FGFR3 和 TERT 突变以及异常 ONECUT2 和 VIM 甲基化的检测，以生成 UC 评分。测试性能在双盲、多中心、前瞻性试验（n = 947；ChiCTR2300076543）中得到验证，并证明敏感性为 91.37%，特异性为 95.09%。对于低级别Ta肿瘤的敏感性达到75.81%，对于高级别Ta及更高阶段（T1至T4）的敏感性超过93%。能够同时识别膀胱和上尿路肿瘤，灵敏度超过 90%。对于良性泌尿系统疾病或非 UC 恶性肿瘤，没有观察到显着的混杂效应。该测试显示，与尿细胞学、NMP22 测试和 UroVysion FISH 相比，其灵敏度有所提高，并且特异性也相当。经桑格测序证实，单靶点准确率大于98%。97.7% 的受试者术后 UC 评分下降。总体而言，UI-Seek 在 UC 早期检测方面表现出了强大的性能和巨大的潜力。