Bladder cancer detection in urine using DNA methylation markers: a technical and prospective preclinical validation

Clinical Epigenetics

Renske D. M. Steenbergen¹  R. Jeroen A. van Moorselaar²  Judith Bosschieter²  Jakko A. Nieuwenhuijzen²  André N. Vis²  Anouk E. Hentschel³  Irene J. Beijert³  Paul C. Kauer⁴  Birgit I. Lissenberg-Witte⁵ 

[1]Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

[2]Department of Urology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

[3]Department of Urology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

[4]Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

[5]Department of Urology, OLVG, Amsterdam, The Netherlands

[6]Epidemiology and Data Science, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

关键词: Biomarkers;    Tumour;    DNA methylation;    Liquid biopsy;    Urinary bladder neoplasms;    Urine;   

DOI  :  10.1186/s13148-022-01240-8

来源: Springer

【 摘 要 】

BackgroundThe development of accurate urinary biomarkers for non-invasive and cost-effective detection of primary and recurrent bladder tumours is recognized as one of the major clinical needs in bladder cancer diagnostics. The purposes of this study were (1) to validate the results of a previous technical comparison by determining the diagnostic performance of nine methylation markers in urine pellet compared to full void urine, and (2) to validate the diagnostic performance of the optimal marker panel GHSR/MAL from a previous exploratory study in a preclinical setting.MethodsUrine samples of 108 patients with bladder cancer and 100 age- and gender-matched controls were prospectively collected for methylation analysis. Urinary methylation levels of the markers FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST and ZIC1 were determined with quantitative methylation-specific PCR in urine pellet. Area under the curves (AUCs) were determined for individual markers and the marker panel GHSR/MAL. The diagnostic performance of the marker panel GHSR/MAL was evaluated in the total study population and in different subgroups of patients with bladder cancer using the Chi-square test. The diagnostic accuracy was assessed by leave-one-out cross-validation.ResultsAll nine urinary methylation markers (FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST and ZIC1) showed significantly higher methylation levels in bladder cancer patients than in controls (p < 0.001). Area under the curves (AUCs) of the nine methylation markers tested in urine pellet were similar to AUCs in full void urine of an independent previous cohort. GHSR/MAL reached an AUC of 0.89 (95% confidence interval [CI] 0.84–0.94), at 80% sensitivity and 93% specificity. Sensitivity of GHSR/MAL increased with higher tumour grades, higher tumour stages, in primary vs. recurrent tumours, and in males vs. females.ConclusionsThis technical validation supports the robustness of DNA methylation analysis in urine pellet and full void urine for the non-invasive detection of bladder cancer. Subsequent preclinical validation confirmed the diagnostic potential of GHSR/MAL. These findings underline the diagnostic potential of the marker panel GHSR/MAL for future bladder cancer diagnostics.

【 授权许可】

CC BY