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Abstract：
BACKGROUND: Urothelial carcinoma (UC) is the second most common urological malignancy. Despite numerous molecular markers have been evaluated during the past decades, no urothelial markers for diagnosis and recurrence monitoring have shown consistent clinical utility.
METHODS: The methylation level of tissue samples from public database and clinical collected were analyzed. Patients with UC and benign diseases of the urinary system (BUD) were enrolled to establish TAGMe (TAG of Methylation) assessment in a training cohort (n = 567) using restriction enzyme-based bisulfite-free qPCR. The performance of TAGMe assessment was further verified in the validation cohort (n = 198). Urine samples from 57 UC patients undergoing postoperative surveillance were collected monthly for six months after surgery to assess the TAGMe methylation.
RESULTS: We identified TAGMe as a potentially novel Universal-Cancer-Only Methylation (UCOM) marker was hypermethylated in multi-type cancers and investigated its application in UC. Restriction enzyme-based bisulfite-free qPCR was used for detection, and the results of which were consistent with gold standard pyrosequencing. Importantly, hypermethylated TAGMe showed excellent sensitivity of 88.9% (95% CI: 81.4-94.1%) and specificity of 90.0% (95% CI: 81.9-95.3%) in efficiently distinguishing UC from BUD patients in urine and also performed well in different clinical scenarios of UC. Moreover, the abnormality of TAGMe as an indicator of recurrence might precede clinical recurrence by three months to one year, which provided an invaluable time window for timely and effective intervention to prevent UC upstaging.
CONCLUSIONS: TAGMe assessment based on a novel single target in urine is effective and easy to perform in UC diagnosis and recurrence monitoring, which may reduce the burden of cystoscopy. Trial registration ChiCTR2100052507. Registered on 30 October 2021.
METHODS: The methylation level of tissue samples from public database and clinical collected were analyzed. Patients with UC and benign diseases of the urinary system (BUD) were enrolled to establish TAGMe (TAG of Methylation) assessment in a training cohort (n = 567) using restriction enzyme-based bisulfite-free qPCR. The performance of TAGMe assessment was further verified in the validation cohort (n = 198). Urine samples from 57 UC patients undergoing postoperative surveillance were collected monthly for six months after surgery to assess the TAGMe methylation.
RESULTS: We identified TAGMe as a potentially novel Universal-Cancer-Only Methylation (UCOM) marker was hypermethylated in multi-type cancers and investigated its application in UC. Restriction enzyme-based bisulfite-free qPCR was used for detection, and the results of which were consistent with gold standard pyrosequencing. Importantly, hypermethylated TAGMe showed excellent sensitivity of 88.9% (95% CI: 81.4-94.1%) and specificity of 90.0% (95% CI: 81.9-95.3%) in efficiently distinguishing UC from BUD patients in urine and also performed well in different clinical scenarios of UC. Moreover, the abnormality of TAGMe as an indicator of recurrence might precede clinical recurrence by three months to one year, which provided an invaluable time window for timely and effective intervention to prevent UC upstaging.
CONCLUSIONS: TAGMe assessment based on a novel single target in urine is effective and easy to perform in UC diagnosis and recurrence monitoring, which may reduce the burden of cystoscopy. Trial registration ChiCTR2100052507. Registered on 30 October 2021.
摘要：
背景：尿路上皮癌（UC）是第二常见的泌尿系统恶性肿瘤。尽管在过去的几十年中已经评估了许多分子标记，没有用于诊断和复发监测的尿路上皮标志物显示出一致的临床效用.
方法：分析来自公共数据库和临床收集的组织样本的甲基化水平。纳入患有UC和泌尿系统良性疾病（BUD）的患者，以使用基于限制酶的无亚硫酸氢盐qPCR在训练队列（n=567）中建立TAGMe（甲基化的TAG）评估。在验证队列中进一步验证了TAGMe评估的性能(n=198)。每月收集57例接受术后监测的UC患者的尿液样本，持续六个月，以评估TAGMe甲基化。
结果：我们确定TAGMe是一种潜在的新型通用仅癌症甲基化（UCOM）标志物，在多类型癌症中被高甲基化，并研究了其在UC中的应用。基于限制性酶的不含亚硫酸氢盐的qPCR用于检测，结果与金标准焦磷酸测序结果一致。重要的是,高甲基化TAGMe在尿液中有效区分UC和BUD患者方面显示出88.9%(95%CI:81.4~94.1%)的良好敏感性和90.0%(95%CI:81.9~95.3%)的特异性,并且在UC的不同临床情况下也表现良好.此外，作为复发指标的TAGMe异常可能先于临床复发3个月至1年,这为及时有效的干预预防UC升级提供了宝贵的时间窗口。
结论：基于尿液新的单一目标的TAGMe评估在UC诊断和复发监测中是有效且易于执行的，这可以减轻膀胱镜检查的负担。试用注册ChiCTR2100052507。2021年10月30日注册。
方法：分析来自公共数据库和临床收集的组织样本的甲基化水平。纳入患有UC和泌尿系统良性疾病（BUD）的患者，以使用基于限制酶的无亚硫酸氢盐qPCR在训练队列（n=567）中建立TAGMe（甲基化的TAG）评估。在验证队列中进一步验证了TAGMe评估的性能(n=198)。每月收集57例接受术后监测的UC患者的尿液样本，持续六个月，以评估TAGMe甲基化。
结果：我们确定TAGMe是一种潜在的新型通用仅癌症甲基化（UCOM）标志物，在多类型癌症中被高甲基化，并研究了其在UC中的应用。基于限制性酶的不含亚硫酸氢盐的qPCR用于检测，结果与金标准焦磷酸测序结果一致。重要的是,高甲基化TAGMe在尿液中有效区分UC和BUD患者方面显示出88.9%(95%CI:81.4~94.1%)的良好敏感性和90.0%(95%CI:81.9~95.3%)的特异性,并且在UC的不同临床情况下也表现良好.此外，作为复发指标的TAGMe异常可能先于临床复发3个月至1年,这为及时有效的干预预防UC升级提供了宝贵的时间窗口。
结论：基于尿液新的单一目标的TAGMe评估在UC诊断和复发监测中是有效且易于执行的，这可以减轻膀胱镜检查的负担。试用注册ChiCTR2100052507。2021年10月30日注册。
