Bladder cancer detection in urine by novel methylation markers.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Urinary Bladder Neoplasms*/urine ; Urinary Bladder Neoplasms*/genetics ; Urinary Bladder Neoplasms*/diagnosis ; DNA Methylation* ; Biomarkers, Tumor*/urine ; Biomarkers, Tumor*/genetics; Humans ; Male ; Female ; Aged ; Middle Aged ; Case-Control Studies ; ROC Curve ; Cystoscopy ; Aged, 80 and over ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/urine ; Sensitivity and Specificity

Although cystoscopy is a reliable tool for detecting bladder cancer (BC) in patients with hematuria, it is invasive, costly and often unnecessary since most patients with hematuria do not have BC. Consequently, developing urinary biomarkers for non-invasive BC detection is a major clinical need. While DNA methylation markers hold promise, diagnostic performance can still be improved. We assessed 11 candidate methylation markers for urinary BC detection. Urine samples from 77 primary BC patients and 69 controls were used for marker selection and training, with independent validation conducted on samples from 63 primary BC patients and 71 controls. Samples were self-collected at home, mailed to the hospital and analyzed via quantitative methylation-specific polymerase chain reaction. Marker performance was evaluated through univariable and multivariable logistic regression analyses. Decision curve analysis (DCA) gauged clinical utility by potential cystoscopy reduction. Evaluation identified three most promising markers: NRN1, GALR1, and HAND2. These markers exhibited significantly elevated methylation levels in BC compared to controls in both cohorts (P < 0.001). The combined marker set demonstrated an area under the curve (AUC) of 0.94 at 84% (95% CI: 76-92%) sensitivity and 96% (95% CI: 91-100%) specificity. Validation yielded nearly equivalent accuracy (AUC 0.89, sensitivity 76% (95% CI: 65-86%), specificity 93% (95% CI: 86-99%)). DCA indicated a potential of 20 to 35% reduction in cystoscopies depending on the clinical scenario. The excellent diagnostic potential of our methylation markers for non-invasive BC detection, emphasizes their significance for future diagnostic strategies.
Competing Interests: Declarations. Competing interests: Renske D. M. Steenbergen holds a minority stake in Self-screen B.V., a spin-off company of Amsterdam UMC, location VUmc, which owns patents and products related to the development of methylation markers for cervical screening. All other authors do not have any competing interest to declare. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Medical Ethics Committee (2018.355 [16-10-2018], WO 18.155 [21-12-2018]) and all participants provided informed written consent before inclusion in the study.
(© 2024. The Author(s).)

Eur Urol Oncol. 2018 Sep;1(4):307-313. (PMID: 31100252)
Epigenomics. 2019 Feb;11(3):337-347. (PMID: 30706728)
Med Decis Making. 2006 Nov-Dec;26(6):565-74. (PMID: 17099194)
BJU Int. 2002 Mar;89(4):347-9. (PMID: 11872022)
Urology. 2019 Apr;126:34-38. (PMID: 30677457)
PLoS One. 2018 Aug 24;13(8):e0200906. (PMID: 30142219)
JAMA. 1990 May 9;263(18):2475-80. (PMID: 2184261)
Clin Epigenetics. 2022 Feb 5;14(1):19. (PMID: 35123558)
Cancers (Basel). 2023 Jan 19;15(3):. (PMID: 36765573)
Br J Urol. 1990 Nov;66(5):503-5. (PMID: 2249120)
BJU Int. 2019 Jun;123(6):959-967. (PMID: 30653818)
J Urol. 2020 Jul;204(1):50-57. (PMID: 31985322)
Trends Genet. 2021 Nov;37(11):1012-1027. (PMID: 34120771)
Eur Urol. 2012 Oct;62(4):620-3. (PMID: 22698575)
Int J Cancer. 2023 Jul 15;153(2):341-351. (PMID: 36912267)
Eur Urol. 2018 Jul;74(1):10-14. (PMID: 29653885)
Eur Urol. 2014 Aug;66(2):253-62. (PMID: 24472711)
J Urol. 2017 Mar;197(3 Pt 1):590-595. (PMID: 27746284)
Clin Epigenetics. 2021 Apr 26;13(1):91. (PMID: 33902700)
BMC Cancer. 2012 Nov 23;12:551. (PMID: 23176198)
Eur Urol. 2022 Jan;81(1):75-94. (PMID: 34511303)
Nat Protoc. 2008;3(6):1101-8. (PMID: 18546601)
Int J Cancer. 2021 May 15;148(10):2481-2488. (PMID: 33426639)
Curr Urol Rep. 2018 Oct 24;19(12):102. (PMID: 30357502)
Biomed Res Int. 2020 Oct 10;2020:7272960. (PMID: 33150179)
Urol Oncol. 2014 Jan;32(1):51.e21-6. (PMID: 24360662)
Urol Oncol. 2015 Feb;33(2):66.e25-31. (PMID: 25037483)
Nat Rev Urol. 2013 Jun;10(6):327-35. (PMID: 23628807)
Clin Epigenetics. 2021 Apr 21;13(1):84. (PMID: 33882992)
Lung Cancer. 2022 Aug;170:156-164. (PMID: 35793574)
Cancer Cytopathol. 2019 Jul;127(7):465-469. (PMID: 31154670)
J Urol. 2011 May;185(5):1698-703. (PMID: 21419446)
Nucleic Acids Res. 2019 Jul 2;47(W1):W561-W565. (PMID: 31114869)

Keywords: Biomarker; Bladder cancer; DNA methylation; Detection; Liquid biopsy; Urinary biomarker; Urine

0 (Biomarkers, Tumor)
0 (Basic Helix-Loop-Helix Transcription Factors)

Date Created: 20241120 Date Completed: 20241120 Latest Revision: 20241125

20241126

PMC11579363

10.1038/s41598-024-77781-0

39567591