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

The 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 co...

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Published in:Clinical epigenetics 2022-02, Vol.14 (1), p.19-19, Article 19
Main Authors: Hentschel, Anouk E, Beijert, Irene J, Bosschieter, Judith, Kauer, Paul C, Vis, André N, Lissenberg-Witte, Birgit I, van Moorselaar, R Jeroen A, Steenbergen, Renske D M, Nieuwenhuijzen, Jakko A
Format: Article
Language:English
Subjects:
Aged
Area Under Curve
Biomarkers
Biomarkers - analysis
Biomarkers - urine
Bladder cancer
Cancer
Cellular biology
Comparative analysis
Deoxyribonucleic acid
Diagnosis
DNA
DNA methylation
DNA Methylation - genetics
Early Detection of Cancer - methods
Early Detection of Cancer - statistics & numerical data
Female
Gender
Genetic aspects
Genetic research
Hematuria
Humans
Male
Methylation
Middle Aged
Netherlands - epidemiology
Oncology, Experimental
Patients
Population studies
Prospective Studies
ROC Curve
Sample size
Sensitivity and Specificity
Software
Tumors
Urinary Bladder Neoplasms - diagnosis
Urinary Bladder Neoplasms - epidemiology
Urinary Bladder Neoplasms - urine
Urine
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cited_by cdi_FETCH-LOGICAL-c497t-6b387ed6ff1d00c23998e8a996339ca3c8a54d839b99d7f00709122ced239f213
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container_start_page 19
container_title Clinical epigenetics
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creator Hentschel, Anouk E
Beijert, Irene J
Bosschieter, Judith
Kauer, Paul C
Vis, André N
Lissenberg-Witte, Birgit I
van Moorselaar, R Jeroen A
Steenbergen, Renske D M
Nieuwenhuijzen, Jakko A
description The 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. Urine 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. All 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 
doi_str_mv 10.1186/s13148-022-01240-8
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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. Urine 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. All 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 &lt; 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. This 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. 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subjects Aged
Area Under Curve
Biomarkers
Biomarkers - analysis
Biomarkers - urine
Bladder cancer
Cancer
Cellular biology
Comparative analysis
Deoxyribonucleic acid
Diagnosis
DNA
DNA methylation
DNA Methylation - genetics
Early Detection of Cancer - methods
Early Detection of Cancer - statistics & numerical data
Female
Gender
Genetic aspects
Genetic research
Hematuria
Humans
Male
Methylation
Middle Aged
Netherlands - epidemiology
Oncology, Experimental
Patients
Population studies
Prospective Studies
ROC Curve
Sample size
Sensitivity and Specificity
Software
Tumors
Urinary Bladder Neoplasms - diagnosis
Urinary Bladder Neoplasms - epidemiology
Urinary Bladder Neoplasms - urine
Urine
title Bladder cancer detection in urine using DNA methylation markers: a technical and prospective preclinical validation
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