Current regimens for the detection and surveillance of bladder cancer (BLCA) 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 BLCA who either had urine collected prior to treatment or during surveillance. Using this targeted sequencing approach, we detected a median of 6 mutations per BLCA patient and observed surprisingly frequent mutations of the PLEKHS1 promoter (46%), suggesting these mutations represent a useful biomarker for detection of BLCA. We detected utDNA pre-treatment in 93% of cases using a tumor mutation-informed approach and in 84% when blinded to tumor mutation status, with 96-100% 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 is less than or equal to 0.006), detecting 100% of BLCA 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 BLCA.
Cancer discovery. 2018 Dec 21 [Epub ahead of print]
Jonathan C Dudley, Joseph Schroers-Martin, Daniel V Lazzareschi, William Y Shi, Simon B Chen, Mohammad Shahrokh 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
Stanford Cancer Institute, Stanford University., Department of Oncology, Stanford University., Department of Pathology, Stanford University., Urology, Stanford University School of Medicine., Stanford Cancer Institute, Stanford University School of Medicine., Department of Radiation Oncology, Washington University in St. Louis School of Medicine., Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University., Pathology, Stanford University., Institute for Stem Cell Biology and Regenerative Medicine, Stanford University., Department of Radiation Oncology, Stanford University .