4.7 Article

Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA

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CANCER DISCOVERY
卷 9, 期 4, 页码 500-509

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-0825

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  1. Joint Initiative for Metrology in Biology [1186777-204-SBARL]
  2. Stanford Pathology Department [1194947-105-DHCRE]
  3. Stanford Cancer Institute
  4. Albert Institute for Bladder Cancer Care and Research
  5. National Cancer Institute [R01CA188298]
  6. U.S. National Institutes of Health Director's New Innovator Award Program [1-DP2-CA186569]
  7. Virginia and D.K. Ludwig Fund for Cancer Research
  8. CRK Faculty Scholar Fund
  9. [NIH S10OD020141]

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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 PLEKH51 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 mutationinformed 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 HIS 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.

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