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Evaluation of an epigenetic profile for the detection of bladder cancer in patients with hematuria

(2016) JOURNAL OF UROLOGY. 195(3). p.601-607
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Abstract
Purpose: Many patients enter the care cycle with gross or microscopic hematuria and undergo cystoscopy to rule out bladder cancer. Sensitivity of this invasive examination is limited, leaving many patients at risk for undetected cancer. To improve current clinical practice more sensitive and noninvasive screening methods should be applied. Materials and Methods: A total of 154 urine samples were collected from patients with hematuria, including 80 without and 74 with bladder cancer. DNA from cells in the urine was epigenetically profiled using 2 independent assays. Methylation specific polymerase chain reaction was performed on TWIST1. SNaPshot (TM) methylation analysis was done for different loci of OTX1 and ONECUT2. Additionally all samples were analyzed for mutation status of TERT (telomerase reverse transcriptase), PIK3CA, FGFR3 (fibroblast growth factor receptor 3), HRAS, KRAS and NRAS. Results: The combination of TWIST1, ONECUT2 (2 loci) and OTX1 resulted in the best overall performing panel. Logistic regression analysis on these methylation markers, mutation status of FGFR3, TERT and HRAS, and patient age resulted in an accurate model with 97% sensitivity, 83% specificity and an AUC of 0.93 (95% CI 0.88-0.98). Internal validation led to an optimism corrected AUC of 0.92. With an estimated bladder cancer prevalence of 5% to 10% in a hematuria cohort the assay resulted in a 99.6% to 99.9% negative predictive value. Conclusions: Epigenetic profiling using TWIST1, ONECUT2 and OTX1 results in a high sensitivity and specificity. Accurate risk prediction might result in less extensive and invasive examination of patients at low risk, thereby reducing unnecessary patient burden and health care costs.
Keywords
risk, diagnosis, ASYMPTOMATIC MICROSCOPIC HEMATURIA, AMERICAN-UROLOGICAL-ASSOCIATION, VOIDED URINE, PRACTICE POLICY, TUMOR-TISSUES, METHYLATION, DIAGNOSIS, CYTOLOGY, GENES, ASSAY, epigenomics, hematuria, urinary bladder neoplasms

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Please use this url to cite or link to this publication:

Chicago
van Kessel, Kim EM, Leander Van Neste, Irene Lurkin, Ellen C Zwarthoff, and Wim Van Criekinge. 2016. “Evaluation of an Epigenetic Profile for the Detection of Bladder Cancer in Patients with Hematuria.” Journal of Urology 195 (3): 601–607.
APA
van Kessel, K. E., Van Neste, L., Lurkin, I., Zwarthoff, E. C., & Van Criekinge, W. (2016). Evaluation of an epigenetic profile for the detection of bladder cancer in patients with hematuria. JOURNAL OF UROLOGY, 195(3), 601–607.
Vancouver
1.
van Kessel KE, Van Neste L, Lurkin I, Zwarthoff EC, Van Criekinge W. Evaluation of an epigenetic profile for the detection of bladder cancer in patients with hematuria. JOURNAL OF UROLOGY. 2016;195(3):601–7.
MLA
van Kessel, Kim EM, Leander Van Neste, Irene Lurkin, et al. “Evaluation of an Epigenetic Profile for the Detection of Bladder Cancer in Patients with Hematuria.” JOURNAL OF UROLOGY 195.3 (2016): 601–607. Print.
@article{7154356,
  abstract     = {Purpose: Many patients enter the care cycle with gross or microscopic hematuria and undergo cystoscopy to rule out bladder cancer. Sensitivity of this invasive examination is limited, leaving many patients at risk for undetected cancer. To improve current clinical practice more sensitive and noninvasive screening methods should be applied. 
Materials and Methods: A total of 154 urine samples were collected from patients with hematuria, including 80 without and 74 with bladder cancer. DNA from cells in the urine was epigenetically profiled using 2 independent assays. Methylation specific polymerase chain reaction was performed on TWIST1. SNaPshot (TM) methylation analysis was done for different loci of OTX1 and ONECUT2. Additionally all samples were analyzed for mutation status of TERT (telomerase reverse transcriptase), PIK3CA, FGFR3 (fibroblast growth factor receptor 3), HRAS, KRAS and NRAS. 
Results: The combination of TWIST1, ONECUT2 (2 loci) and OTX1 resulted in the best overall performing panel. Logistic regression analysis on these methylation markers, mutation status of FGFR3, TERT and HRAS, and patient age resulted in an accurate model with 97\% sensitivity, 83\% specificity and an AUC of 0.93 (95\% CI 0.88-0.98). Internal validation led to an optimism corrected AUC of 0.92. With an estimated bladder cancer prevalence of 5\% to 10\% in a hematuria cohort the assay resulted in a 99.6\% to 99.9\% negative predictive value. 
Conclusions: Epigenetic profiling using TWIST1, ONECUT2 and OTX1 results in a high sensitivity and specificity. Accurate risk prediction might result in less extensive and invasive examination of patients at low risk, thereby reducing unnecessary patient burden and health care costs.},
  author       = {van Kessel, Kim EM and Van Neste, Leander and Lurkin, Irene and Zwarthoff, Ellen C and Van Criekinge, Wim},
  issn         = {0022-5347},
  journal      = {JOURNAL OF UROLOGY},
  keyword      = {risk,diagnosis,ASYMPTOMATIC MICROSCOPIC HEMATURIA,AMERICAN-UROLOGICAL-ASSOCIATION,VOIDED URINE,PRACTICE POLICY,TUMOR-TISSUES,METHYLATION,DIAGNOSIS,CYTOLOGY,GENES,ASSAY,epigenomics,hematuria,urinary bladder neoplasms},
  language     = {eng},
  number       = {3},
  pages        = {601--607},
  title        = {Evaluation of an epigenetic profile for the detection of bladder cancer in patients with hematuria},
  url          = {http://dx.doi.org/10.1016/j.juro.2015.08.085},
  volume       = {195},
  year         = {2016},
}

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