Urinary DNA Methylation Test for Bladder Cancer Diagnosis.

Importance: An accurate noninvasive biomarker test is needed for the early diagnosis of bladder cancer. Objective: To evaluate the performance of a urinary DNA methylation test (PENK methylation) and compare its diagnostic accuracy with that of the nuclear matrix protein 22 (NMP22) test or urine cytology test. Design, Setting, and Participants: In this prospective multicenter study at 10 sites in the Republic of Korea, individuals 40 years and older with hematuria undergoing cystoscopy within 3 months between March 11, 2022, and May 30, 2024, participated. The study participants were evaluated for bladder cancer using a urinary DNA methylation test. Exposure: Urinary DNA methylation test, NMP22 test, and urine cytology test. Main Outcomes and Measures: The primary outcomes were the sensitivity and specificity of the urinary DNA methylation test for high-grade or invasive bladder cancer. Secondary objectives included the accuracy of the test for overall bladder cancer (all stages and grades) and the comparison of sensitivities and specificities for bladder cancer between the urinary DNA methylation test and the NMP22 test or urine cytology test. Results: Among the 1099 participants, 614 (55.9%) were male; participants had a mean (SD) age of 65 (10) years. Of the 1099 participants, 219 and 176 participants had bladder cancer and high-grade or invasive bladder cancer, respectively. The urinary DNA methylation test had sensitivity and specificity for high-grade or invasive bladder cancer of 89.2% (95% CI, 84.6%-93.8%) and 87.8% (95% CI, 85.6%-89.9%), respectively. Sensitivity and specificity for overall bladder cancer were 78.1% (95% CI, 72.6%-83.6%) and 88.8% (95% CI, 86.7%-90.8%), respectively. The positive predictive value for high-grade or invasive bladder cancer was 61.3% (95% CI, 55.4%-67.3%), and the negative predictive value was 97.6% (95% CI, 96.6%-98.7%). In comparison with the NMP22 test or urine cytology test, the urinary DNA methylation test showed significantly superior sensitivity for high-grade or invasive bladder cancer and overall bladder cancer. Conclusions and Relevance: In this prospective multicenter study of individuals with hematuria, the urinary DNA methylation test showed 89% sensitivity for detecting high-grade or invasive bladder cancer, outperforming the NMP22 test or urine cytology test with high specificity. While this test had an excellent negative predictive value, its positive predictive value was suboptimal.