Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA.

Abstract

Current regimens for the detection and surveillance of bladder cancer are invasive and have suboptimal sensitivity. Here, we present a novel high-throughput sequencing (HTS) method for detection of urine tumor DNA (utDNA) called utDNA CAPP-Seq (uCAPP-Seq) and apply it to 67 healthy adults and 118 patients with early-stage bladder cancer who had urine collected either prior to treatment or during surveillance. Using this targeted sequencing approach, we detected a median of 6 mutations per patient with bladder cancer and observed surprisingly frequent mutations of the PLEKHS1 promoter (46%), suggesting these mutations represent a useful biomarker for detection of bladder cancer. We detected utDNA pretreatment in 93% of cases using a tumor mutation-informed approach and in 84% when blinded to tumor mutation status, with 96% to 100% specificity. In the surveillance setting, we detected utDNA in 91% of patients who ultimately recurred, with utDNA detection preceding clinical progression in 92% of cases. uCAPP-Seq outperformed a commonly used ancillary test (UroVysion, P = 0.02) and cytology and cystoscopy combined (P ≤ 0.006), detecting 100% of bladder cancer cases detected by cytology and 82% that cytology missed. Our results indicate that uCAPP-Seq is a promising approach for early detection and surveillance of bladder cancer. SIGNIFICANCE: This study shows that utDNA can be detected using HTS with high sensitivity and specificity in patients with early-stage bladder cancer and during post-treatment surveillance, significantly outperforming standard diagnostic modalities and facilitating noninvasive detection, genotyping, and monitoring.This article is highlighted in the In This Issue feature, p. 453.

• Authors: Jonathan C Dudley, Joseph Schroers-Martin, Daniel V Lazzareschi, William Y Shi, Simon B Chen, Mohammad S Esfahani, Dharati Trivedi, Jacob J Chabon, Aadel A Chaudhuri, Henning Stehr, Chih Long Liu, Harumi Lim, Helio A Costa, Barzin Y Nabet, Mandy L Y Sin, Joseph C Liao, Ash A Alizadeh, Maximilian Diehn
• Journal: Cancer discovery (Cancer Discov) Vol. 9 Issue 4 Pg. 500-509 (04 2019) ISSN: 2159-8290 [Electronic] United States
• PMID: 30578357 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• DNA, Neoplasm

Topics

• Biomarkers, Tumor (metabolism)
• DNA, Neoplasm (urine)
• Female
• Humans
• Male
• Urinary Bladder Neoplasms (diagnosis, urine)