Evaluation of an Epigenetic Profile for the Detection of Bladder Cancer in Hematuria Patients

Many patients enter the care cycle with gross or microscopic hematuria and undergo a cystoscopy to rule out bladder cancer. Sensitivity of this invasive examination is limited, leaving many patients at risk of having undetected cancer.

To improve upon current clinical practice more sensitive and non-invasive screening methods should be applied.

A total of 154 urine samples were collected from hematuria patients without (n=80) and with (n=74) bladder cancer. DNA from cells in the urine was epigenetically profiled using two independent assays. Methylation-specific PCR (MSP) was performed on TWIST1. SNaPshot methylation analysis was performed for different loci of OTX1 and ONECUT2. Additionally, all samples were analyzed for mutation status of TERT, PIK3CA, FGFR3, HRAS, KRAS and NRAS.

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 age resulted in an accurate model with a sensitivity of 97% (83% specificity). The area under the curve (AUC) was 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 5-10% in a hematuria cohort the assay results in a negative predictive value (NPV) of 99. 6% to 99. 9%.

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 low-risk patients, hereby reducing unnecessary patient burden and healthcare costs.

The Journal of urology. 2015 Aug 28 [Epub ahead of print]

Kim E M van Kessel, Leander Van Neste, Irene Lurkin, Ellen C Zwarthoff, Wim Van Criekinge

Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands; The Netherlands. , MDxHealth, Inc. , Irvine, CA, USA; Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. , Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands; The Netherlands. , Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands; The Netherlands. , MDxHealth, Inc. , Irvine, CA, USA; Laboratory of Bioinformatics and Computational Genomics, Ghent University, Belgium. 

PubMed