Urine RNA Panel Supports Less Invasive Bladder Cancer Surveillance

Cystoscopy is central to bladder cancer detection and surveillance, but repeated procedures carry practical and patient burdens, including discomfort, anxiety, and frequent clinic visits. A prospective study published in the Journal of Clinical Investigation suggests that a 3-gene urine RNA panel could help clinicians decide when cystoscopy should be expedited and when it may be reasonable to defer an invasive evaluation.

A Multicenter Test of Detection and Surveillance
The investigators of the study validated the urine RNA panel, or uRNAp, across Stanford Health Care and the Veterans Affairs Palo Alto Health Care System. The assay uses RT-qPCR to measure expression of ROBO1, CRH, and IGF2 in urine sediment and generates a probability score for urothelial carcinoma.

The study prospectively collected 2,178 urine samples from 856 patients between 2019 and 2025. After excluding samples with inadequate cellularity or nonurothelial histology, the analysis included 547 samples from 529 patients undergoing initial evaluation and 1,543 samples from 447 patients receiving surveillance after a previous bladder cancer diagnosis. Most participants were older adults, and men comprised 91% of the detection cohort and 83% of the surveillance cohort.

In the detection cohort, 123 patients had newly diagnosed bladder cancer, including 93 high-grade tumors. At the prespecified positivity threshold, uRNAp achieved 98% sensitivity, 51% specificity, a negative predictive value of 96%, and an area under the receiver operating characteristic curve of 0.92.

The surveillance cohort included 286 histologically confirmed recurrences. uRNAp detected 94% overall, including 99% of high-grade recurrences and 86% of low-grade recurrences. Specificity was 43%, the negative predictive value was 97%, and the area under the curve was 0.81. By comparison, urine cytology had 33% sensitivity in both cohorts, although its specificity remained 99%.

Performance Tracked with Tumor Risk
uRNAp scores rose with both tumor size and grade, strengthening the case that the assay reflects clinically relevant disease burden rather than simply the presence or absence of malignant cells. Large high-grade tumors produced the highest scores, while small low-grade tumors produced the lowest.

This pattern also explains most missed cases. In the detection cohort, 2 of the 3 false-negative results occurred in tumors smaller than 1 cm and low grade. In surveillance, 17 of 18 false negatives were low-grade Ta recurrences, most of them small. The only missed high-grade surveillance recurrence was a small focus of carcinoma in situ.

The cystoscopic images included in the study reinforce this point: most false-negative lesions were visually subtle, small, low-grade papillary tumors, while one missed high-grade tumor was confined within a bladder diverticulum. That anatomical location may have limited shedding of tumor cells into urine and highlights a potential limitation of any urine-based assay.

Notably, uRNAp also identified all 13 upper tract urothelial carcinomas detected during surveillance, including 9 high-grade tumors. However, this subgroup was small, and the authors appropriately call for a dedicated upper tract validation cohort before drawing firm conclusions.

Where the Assay May Fit
The test’s strength lies in sensitivity and negative predictive value, not confirmatory specificity. A negative result may help support longer intervals between cystoscopies in selected low- or intermediate-risk patients, particularly when prior surveillance has been repeatedly negative. A positive result, especially at a high score, could justify expedited cystoscopy or closer evaluation.

Still, the modest specificity means many positive results will occur without contemporaneously confirmed cancer. Some may reflect inflammation or benign lesions, while others could represent disease that is not yet visible. The study documented several patients with high scores and initially negative evaluations who were later diagnosed with high-grade disease or carcinoma in situ, but this finding remains exploratory.

The study was observational, enrolled patients at only 2 health systems, and included a predominantly male population. uRNAp is also not yet available as a CLIA-certified assay. Randomized implementation studies will be needed to determine whether using the test to guide cystoscopy schedules safely reduces procedures, costs, and patient burden without delaying clinically important diagnoses.

For now, uRNAp appears best positioned as an adjunct rather than a replacement for cystoscopy. Its high sensitivity, especially for high-grade recurrence, supports further study as a triage tool in risk-adapted bladder cancer surveillance.

Reference:
Mach KE, Kornberg Z, Shkolyar E, et al. Large multicenter validation of urine RNA profile for urothelial carcinoma detection and surveillance. J Clin Invest. 2026;136(11):e203094. Published April 9, 2026. doi:10.1172/JCI203094.